{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:11:46Z","timestamp":1792699906190,"version":"4.5.0"},"reference-count":145,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100019779","name":"Qatar National Library","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100019779","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Inflammopharmacol"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Raynaud\u2019s phenomenon is a peripheral vascular disorder characterized by exaggerated vasoconstrictive response to certain stimuli, most typically cold exposure and emotional stress. Interestingly, Raynaud\u2019s phenomenon incidence is significantly higher in premenopausal females compared to age-matched males, highlighting a role of the female hormone, estrogen, in Raynaud\u2019s phenomenon pathogenesis. Indeed, estrogen plays a fundamental role in potentiating the expression and function of \u03b1<jats:sub>2C<\/jats:sub> adrenoceptor (\u03b1<jats:sub>2C<\/jats:sub>-AR), the sole mediator of local cooling-induced vasoconstriction. Due to the mosaic nature of Raynaud\u2019s phenomenon involving vascular, hormonal, and neuronal factors, as well as due to the lack of an appropriate animal model, the pathogenesis of Raynaud\u2019s phenomenon is not fully elucidated. Consequently, despite various therapeutic approaches aimed at mitigating symptoms of Raynaud\u2019s phenomenon, a definitive treatment for Raynaud\u2019s phenomenon is quite challenging and remains an unmet need. Therefore, a better understanding of the underlying pathophysiologic mechanisms of Raynaud\u2019s phenomenon is crucial to better delineate pharmacotherapeutic targets to help fight this elusive disease. In this paper, we dissect the molecular and cellular mechanisms underlying Raynaud\u2019s phenomenon and its risk factors, and we shed more light on the role of estrogen. We also explore traditional and current therapeutic approaches, including pharmacologic and non-pharmacologic treatments. In addition, we discuss how the advancement in molecular research offered promising avenues of Raynaud\u2019s phenomenon treatment, namely drug repurposing and molecular targeting. Nonetheless, enhanced awareness, precaution, and good patient compliance are critically important in preventing the progression of Raynaud\u2019s phenomenon and reducing its severity.<\/jats:p>","DOI":"10.1007\/s10787-025-01792-0","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T11:12:22Z","timestamp":1749726742000},"page":"3637-3651","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cold responses and hormonal echoes: a comprehensive view of Raynaud\u2019s vascular dysfunction"],"prefix":"10.1007","volume":"33","author":[{"given":"Manal","family":"Fardoun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odette","family":"El Ghawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christie","family":"Dib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leen","family":"Jaradi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie Therese","family":"Chaddad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Dehaini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3004-5675","authenticated-orcid":false,"given":"Ali H.","family":"Eid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"key":"1792_CR1","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1124\/pr.113.008219","volume":"66","author":"A Ahles","year":"2014","unstructured":"Ahles A, Engelhardt S (2014) Polymorphic variants of adrenoceptors: pharmacology, physiology, and role in disease. Pharmacol Rev 66:598\u2013637","journal-title":"Pharmacol Rev"},{"key":"1792_CR2","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1024\/0301-1526.30.4.281","volume":"30","author":"M Al-Awami","year":"2001","unstructured":"Al-Awami M, Schillinger M, Gschwandtner ME, Maca T, Haumer M, Minar E (2001) Low level laser treatment of primary and secondary Raynaud\u2019s phenomenon. Vasa 30:281\u2013284","journal-title":"Vasa"},{"key":"1792_CR3","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/201787","volume":"2011","author":"K Arefiev","year":"2011","unstructured":"Arefiev K, Fiorentino DF, Chung L (2011) Endothelin receptor antagonists for the treatment of Raynaud\u2019s phenomenon and digital ulcers in systemic sclerosis. Int J Rheumatol 2011:201787","journal-title":"Int J Rheumatol"},{"key":"1792_CR4","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1161\/01.RES.0000128407.45014.58","volume":"94","author":"SR Bailey","year":"2004","unstructured":"Bailey SR, Eid AH, Mitra S, Flavahan S, Flavahan NA (2004) Rho kinase mediates cold-induced constriction of cutaneous arteries: role of alpha2C-adrenoceptor translocation. Circ Res 94:1367\u20131374","journal-title":"Circ Res"},{"key":"1792_CR5","doi-asserted-by":"publisher","first-page":"H243","DOI":"10.1152\/ajpheart.01305.2004","volume":"289","author":"SR Bailey","year":"2005","unstructured":"Bailey SR, Mitra S, Flavahan S, Flavahan NA (2005) Reactive oxygen species from smooth muscle mitochondria initiate cold-induced constriction of cutaneous arteries. Am J Physiol Heart Circ Physiol 289:H243\u2013H250","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"1792_CR6","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1080\/23328940.2020.1735927","volume":"7","author":"FC Baker","year":"2020","unstructured":"Baker FC, Siboza F, Fuller A (2020) Temperature regulation in women: effects of the menstrual cycle. Temperature (Austin) 7:226\u2013262","journal-title":"Temperature (Austin)"},{"key":"1792_CR7","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.jaad.2008.06.004","volume":"59","author":"R Bakst","year":"2008","unstructured":"Bakst R, Merola JF, Franks AG Jr, Sanchez M (2008) Raynaud\u2019s phenomenon: pathogenesis and management. J Am Acad Dermatol 59:633\u2013653","journal-title":"J Am Acad Dermatol"},{"key":"1792_CR8","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1097\/PRS.0000000000000104","volume":"133","author":"J Bank","year":"2014","unstructured":"Bank J, Fuller SM, Henry GI, Zachary LS (2014) Fat grafting to the hand in patients with Raynaud phenomenon: a novel therapeutic modality. Plast Reconstr Surg 133:1109\u20131118","journal-title":"Plast Reconstr Surg"},{"key":"1792_CR9","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1024\/0301-1526\/a000661","volume":"46","author":"J Belch","year":"2017","unstructured":"Belch J, Carlizza A, Carpentier PH, Constans J, Khan F, Wautrecht JC, Visona A, Heiss C, Brodeman M, Pecsvarady Z, Roztocil K, Colgan MP, Vasic D, Gottsater A, Amann-Vesti B, Chraim A, Poredos P, Olinic DM, Madaric J, Nikol S, Herrick AL, Sprynger M, Klein-Weigel P, Hafner F, Staub D, Zeman Z (2017) ESVM guidelines\u2014the diagnosis and management of Raynaud\u2019s phenomenon. Vasa 46:413\u2013423","journal-title":"Vasa"},{"key":"1792_CR10","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1007\/s10067-024-07238-2","volume":"44","author":"R Bixio","year":"2024","unstructured":"Bixio R, Mastropaolo F, Appoloni M, Bertelle D, Bertoldo E, Morciano A, Di Donato S, Adami G, Viapiana O, Rossini M, Luca I (2024) Barnidipine as a potential alternative treatment for Raynaud\u2019s phenomenon secondary to systemic sclerosis: a retrospective pilot study. Clin Rheumatol 44:299\u2013304","journal-title":"Clin Rheumatol"},{"key":"1792_CR11","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1177\/1358863X9700200404","volume":"2","author":"FN Brand","year":"1997","unstructured":"Brand FN, Larson MG, Kannel WB, McGuirk JM (1997) The occurrence of Raynaud\u2019s phenomenon in a general population: the Framingham Study. Vasc Med 2:296\u2013301","journal-title":"Vasc Med"},{"key":"1792_CR12","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1097\/FJC.0b013e31823c0bed","volume":"59","author":"SJ Bredie","year":"2012","unstructured":"Bredie SJ, Jong MC (2012) No significant effect of ginkgo biloba special extract EGb 761 in the treatment of primary Raynaud phenomenon: a randomized controlled trial. J Cardiovasc Pharmacol 59:215\u2013221","journal-title":"J Cardiovasc Pharmacol"},{"key":"1792_CR13","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1023\/A:1010758530555","volume":"24","author":"KM Brown","year":"2001","unstructured":"Brown KM, Middaugh SJ, Haythornthwaite JA, Bielory L (2001) The effects of stress, anxiety, and outdoor temperature on the frequency and severity of Raynaud\u2019s attacks: the Raynaud\u2019s Treatment Study. J Behav Med 24:137\u2013153","journal-title":"J Behav Med"},{"key":"1792_CR14","unstructured":"Bulsara KG, Patel P, Cassagnol M (2025) Amlodipine. StatPearls. Treasure Island (FL) ineligible companies. Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies. Disclosure: Manouchkathe Cassagnol declares no relevant financial relationships with ineligible companies"},{"key":"1792_CR15","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1001\/archinte.166.2.231","volume":"166","author":"E Caglayan","year":"2006","unstructured":"Caglayan E, Huntgeburth M, Karasch T, Weihrauch J, Hunzelmann N, Krieg T, Erdmann E, Rosenkranz S (2006) Phosphodiesterase type 5 inhibition is a novel therapeutic option in Raynaud disease. Arch Intern Med 166:231\u2013233","journal-title":"Arch Intern Med"},{"key":"1792_CR16","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1016\/S0025-7125(16)30623-X","volume":"73","author":"MB Cardelli","year":"1989","unstructured":"Cardelli MB, Kleinsmith DM (1989) Raynaud\u2019s phenomenon and disease. Med Clin North Am 73:1127\u20131141","journal-title":"Med Clin North Am"},{"issue":"Suppl 3","key":"1792_CR17","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/bjc.1998.750","volume":"78","author":"J Carmichael","year":"1998","unstructured":"Carmichael J (1998) The role of gemcitabine in the treatment of other tumours. Br J Cancer 78(Suppl 3):21\u201325","journal-title":"Br J Cancer"},{"key":"1792_CR18","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1136\/bmj.295.6589.51-a","volume":"295","author":"AD Chant","year":"1987","unstructured":"Chant AD (1987) Exaggerated postural vasoconstrictor reflex in Raynaud\u2019s phenomenon. Br Med J (Clin Res Ed) 295:51","journal-title":"Br Med J (Clin Res Ed)"},{"issue":"109","key":"1792_CR19","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1152\/japplphysiol.00298.2010","volume":"1985","author":"N Charkoudian","year":"2010","unstructured":"Charkoudian N (2010) Mechanisms and modifiers of reflex induced cutaneous vasodilation and vasoconstriction in humans. J Appl Physiol 1985(109):1221\u20131228","journal-title":"J Appl Physiol"},{"key":"1792_CR20","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1136\/oem.57.5.341","volume":"57","author":"M Cherniack","year":"2000","unstructured":"Cherniack M, Clive J, Seidner A (2000) Vibration exposure, smoking, and vascular dysfunction. Occup Environ Med 57:341\u2013347","journal-title":"Occup Environ Med"},{"key":"1792_CR21","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1177\/1358863X20983455","volume":"26","author":"E Choi","year":"2021","unstructured":"Choi E, Henkin S (2021) Raynaud\u2019s phenomenon and related vasospastic disorders. Vasc Med 26:56\u201370","journal-title":"Vasc Med"},{"key":"1792_CR22","doi-asserted-by":"publisher","first-page":"H1075","DOI":"10.1152\/ajpheart.2000.278.4.H1075","volume":"278","author":"MA Chotani","year":"2000","unstructured":"Chotani MA, Flavahan S, Mitra S, Daunt D, Flavahan NA (2000) Silent alpha(2C)-adrenergic receptors enable cold-induced vasoconstriction in cutaneous arteries. Am J Physiol Heart Circ Physiol 278:H1075\u2013H1083","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"1792_CR23","first-page":"1341","volume":"30","author":"ME Clowse","year":"2003","unstructured":"Clowse ME, Wigley FM (2003) Digital necrosis related to carboplatin and gemcitabine therapy in systemic sclerosis. J Rheumatol 30:1341\u20131343","journal-title":"J Rheumatol"},{"key":"1792_CR24","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1093\/rheumatology\/40.9.1038","volume":"40","author":"B Coleiro","year":"2001","unstructured":"Coleiro B, Marshall SE, Denton CP, Howell K, Blann A, Welsh KI, Black CM (2001) Treatment of Raynaud\u2019s phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology (Oxford) 40:1038\u20131043","journal-title":"Rheumatology (Oxford)"},{"key":"1792_CR25","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1093\/occmed\/kqab158","volume":"72","author":"R Cooke","year":"2022","unstructured":"Cooke R, Lawson I, Gillibrand S, Cooke A (2022) Carpal tunnel syndrome and Raynaud\u2019s phenomenon: a narrative review. Occup Med (Lond) 72:170\u2013176","journal-title":"Occup Med (Lond)"},{"key":"1792_CR26","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1177\/1060028016660324","volume":"50","author":"JE Cruz","year":"2016","unstructured":"Cruz JE, Ward A, Anthony S, Chang S, Bae HB, Hermes-Desantis ER (2016) Evidence for the use of epoprostenol to treat Raynaud\u2019s phenomenon with or without digital ulcers. Ann Pharmacother 50:1060\u20131067","journal-title":"Ann Pharmacother"},{"key":"1792_CR27","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.jaad.2022.06.1199","volume":"90","author":"P Curtiss","year":"2024","unstructured":"Curtiss P, Svigos K, Schwager Z, Lo Sicco K, Franks AG Jr (2024) Part I: Epidemiology, pathophysiology, and clinical considerations of primary and secondary Raynaud\u2019s phenomenon. J Am Acad Dermatol 90:223\u2013234","journal-title":"J Am Acad Dermatol"},{"key":"1792_CR28","first-page":"207","volume":"154","author":"V D'Alessandro","year":"2003","unstructured":"D\u2019Alessandro V, Errico M, Varriale A, Greco A, De Cata A, Carnevale V, Grilli M, De Luca P, Brucoli I, Susi M, Camagna A (2003) Case report: Acro-necrosis of the upper limbs caused by gemcitabine therapy. Clin Ter 154:207\u2013210","journal-title":"Clin Ter"},{"key":"1792_CR29","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2023.107192","volume":"151","author":"M Del Carmen Gonzalez-Montelongo","year":"2023","unstructured":"Del Carmen Gonzalez-Montelongo M, Meades JL, Fortuny-Gomez A, Fountain SJ (2023) Neuropeptide Y: direct vasoconstrictor and facilitatory effects on P2X1 receptor-dependent vasoconstriction in human small abdominal arteries. Vascul Pharmacol 151:107192","journal-title":"Vascul Pharmacol"},{"key":"1792_CR30","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1136\/ard-2024-226430","volume":"84","author":"F Del Galdo","year":"2025","unstructured":"Del Galdo F, Lescoat A, Conaghan PG, Bertoldo E, Colic J, Santiago T, Suliman YA, Matucci-Cerinic M, Gabrielli A, Distler O, Hoffmann-Vold AM, Castellvi I, Balbir-Gurman A, Vonk M, Ananyeva L, Rednic S, Tarasova A, Ostojic P, Boyadzhieva V, El Aoufy K, Farrington S, Galetti I, Denton CP, Kowal-Bielecka O, Mueller-Ladner U, Allanore Y (2025) EULAR recommendations for the treatment of systemic sclerosis: 2023 update. Ann Rheum Dis 84:29\u201340","journal-title":"Ann Rheum Dis"},{"key":"1792_CR31","doi-asserted-by":"publisher","first-page":"2370","DOI":"10.1002\/art.40242","volume":"69","author":"CP Denton","year":"2017","unstructured":"Denton CP, Hachulla E, Riemekasten G, Schwarting A, Frenoux JM, Frey A, Le Brun FO, Herrick AL, Raynaud Study Investigators (2017) Efficacy and safety of Selexipag in adults with Raynaud\u2019s phenomenon secondary to systemic sclerosis: a randomized, placebo-controlled, phase II study. Arthritis Rheumatol 69:2370\u20132379","journal-title":"Arthritis Rheumatol"},{"key":"1792_CR32","doi-asserted-by":"crossref","unstructured":"Dhaliwal K, Griffin M, Denton CP, Butler PEM (2018) The novel use of botulinum toxin A for the treatment of Raynaud\u2019s phenomenon in the toes. BMJ Case Rep 2018","DOI":"10.1136\/bcr-2017-219348"},{"key":"1792_CR33","doi-asserted-by":"publisher","first-page":"899","DOI":"10.3899\/jrheum.2024-0103","volume":"51","author":"M Di Battista","year":"2024","unstructured":"Di Battista M, Della Rossa A, Mosca M (2024) Long-term data on efficacy and safety of Selexipag for digital systemic sclerosis vasculopathy. J Rheumatol 51:899\u2013903","journal-title":"J Rheumatol"},{"key":"1792_CR34","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/0002-9343(89)90261-1","volume":"86","author":"RA Digiacomo","year":"1989","unstructured":"Digiacomo RA, Kremer JM, Shah DM (1989) Fish-oil dietary supplementation in patients with Raynaud\u2019s phenomenon: a double-blind, controlled, prospective study. Am J Med 86:158\u2013164","journal-title":"Am J Med"},{"key":"1792_CR35","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1002\/ana.20769","volume":"59","author":"V Donadio","year":"2006","unstructured":"Donadio V, Nolano M, Provitera V, Stancanelli A, Lullo F, Liguori R, Santoro L (2006) Skin sympathetic adrenergic innervation: an immunofluorescence confocal study. Ann Neurol 59:376\u2013381","journal-title":"Ann Neurol"},{"key":"1792_CR36","doi-asserted-by":"publisher","first-page":"2646","DOI":"10.1002\/1529-0131(199912)42:12<2646::AID-ANR21>3.0.CO;2-T","volume":"42","author":"M Dziadzio","year":"1999","unstructured":"Dziadzio M, Denton CP, Smith R, Howell K, Blann A, Bowers E, Black CM (1999) Losartan therapy for Raynaud\u2019s phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum 42:2646\u20132655","journal-title":"Arthritis Rheum"},{"key":"1792_CR37","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1042\/CS20040262","volume":"109","author":"MJ Easter","year":"2005","unstructured":"Easter MJ, Marshall JM (2005) Contribution of prostanoids to endothelium-dependent vasodilatation in the digital circulation of women with primary Raynaud\u2019s disease. Clin Sci (Lond) 109:45\u201354","journal-title":"Clin Sci (Lond)"},{"key":"1792_CR38","doi-asserted-by":"publisher","first-page":"H1955","DOI":"10.1152\/ajpheart.00306.2007","volume":"293","author":"AH Eid","year":"2007","unstructured":"Eid AH, Maiti K, Mitra S, Chotani MA, Flavahan S, Bailey SR, Thompson-Torgerson CS, Flavahan NA (2007) Estrogen increases smooth muscle expression of alpha2C-adrenoceptors and cold-induced constriction of cutaneous arteries. Am J Physiol Heart Circ Physiol 293:H1955\u2013H1961","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"1792_CR39","doi-asserted-by":"publisher","first-page":"H266","DOI":"10.1152\/ajpheart.00084.2008","volume":"295","author":"AH Eid","year":"2008","unstructured":"Eid AH, Chotani MA, Mitra S, Miller TJ, Flavahan NA (2008) Cyclic AMP acts through Rap1 and JNK signaling to increase expression of cutaneous smooth muscle alpha2C-adrenoceptors. Am J Physiol Heart Circ Physiol 295:H266\u2013H272","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"1792_CR40","doi-asserted-by":"publisher","first-page":"2409","DOI":"10.2174\/0929867327666200903114154","volume":"28","author":"N El-Hachem","year":"2021","unstructured":"El-Hachem N, Fardoun MM, Slika H, Baydoun E, Eid AH (2021) Repurposing cilostazol for Raynaud\u2019s phenomenon. Curr Med Chem 28:2409\u20132417","journal-title":"Curr Med Chem"},{"key":"1792_CR41","first-page":"CD002069","volume":"2","author":"H Ennis","year":"2016","unstructured":"Ennis H, Hughes M, Anderson ME, Wilkinson J, Herrick AL (2016) Calcium channel blockers for primary Raynaud\u2019s phenomenon. Cochrane Database Syst Rev 2:CD002069","journal-title":"Cochrane Database Syst Rev"},{"key":"1792_CR42","first-page":"169","volume":"39","author":"P Falappa","year":"1982","unstructured":"Falappa P, Magnavita N, Bergamaschi A, Colavita N (1982) Angiographic study of digital arteries in workers exposed to vinyl chloride. Br J Ind Med 39:169\u2013172","journal-title":"Br J Ind Med"},{"key":"1792_CR43","doi-asserted-by":"publisher","first-page":"438","DOI":"10.3389\/fphar.2016.00438","volume":"7","author":"MM Fardoun","year":"2016","unstructured":"Fardoun MM, Nassif J, Issa K, Baydoun E, Eid AH (2016) Raynaud\u2019s phenomenon: a brief review of the underlying mechanisms. Front Pharmacol 7:438","journal-title":"Front Pharmacol"},{"key":"1792_CR44","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2020.106690","volume":"131","author":"MM Fardoun","year":"2020","unstructured":"Fardoun MM, Issa K, Maaliki D, Nasser SA, Baydoun E, Eid AH (2020) Estrogen increases expression of vascular alpha 2C adrenoceptor through the cAMP\/Epac\/JNK\/AP-1 pathway and potentiates cold-induced vasoconstriction. Vascul Pharmacol 131:106690","journal-title":"Vascul Pharmacol"},{"key":"1792_CR45","doi-asserted-by":"publisher","first-page":"1061374","DOI":"10.3389\/fphar.2022.1061374","volume":"13","author":"M Fardoun","year":"2022","unstructured":"Fardoun M, Mondello S, Kobeissy F, Eid AH (2022) G protein estrogen receptor as a potential therapeutic target in Raynaud\u2019s phenomenon. Front Pharmacol 13:1061374","journal-title":"Front Pharmacol"},{"key":"1792_CR46","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1097\/FJC.0000000000001489","volume":"82","author":"M Fardoun","year":"2023","unstructured":"Fardoun M, Nasser SA, El-Yazbi AF, Eid AH (2023) GPER acts through the cAMP\/Epac\/JNK\/AP-1 pathway to induce transcription of alpha 2C adrenoceptor in human microvascular smooth muscle cells. J Cardiovasc Pharmacol 82:470\u2013479","journal-title":"J Cardiovasc Pharmacol"},{"key":"1792_CR47","doi-asserted-by":"publisher","first-page":"133","DOI":"10.2174\/0929867330666230220123237","volume":"31","author":"M Fardoun","year":"2024","unstructured":"Fardoun M, Kobeissy F, Eid AH (2024) Estrogen receptor and the gender bias in Raynaud\u2019s phenomenon. Curr Med Chem 31:133\u2013137","journal-title":"Curr Med Chem"},{"key":"1792_CR48","doi-asserted-by":"crossref","unstructured":"Fardoun MM, Matar A, Khachab M, Dakroub A, Eid AH (2025) Cigarette smoke extract induces p38-mediated expression and ROS\/rho-mediated translocation of alpha 2C adrenoceptor in human microvascular smooth muscle cells. Prog Cardiovasc Dis","DOI":"10.1016\/j.pcad.2025.01.002"},{"key":"1792_CR49","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1038\/nrrheum.2014.195","volume":"11","author":"NA Flavahan","year":"2015","unstructured":"Flavahan NA (2015) A vascular mechanistic approach to understanding Raynaud phenomenon. Nat Rev Rheumatol 11:146\u2013158","journal-title":"Nat Rev Rheumatol"},{"key":"1792_CR50","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1007\/s10038-006-0038-9","volume":"51","author":"L Fontana","year":"2006","unstructured":"Fontana L, Marion MJ, Ughetto S, Catilina P (2006) Glutathione S-transferase M1 and GST T1 genetic polymorphisms and Raynaud\u2019s phenomenon in French vinyl chloride monomer-exposed workers. J Hum Genet 51:879\u2013886","journal-title":"J Hum Genet"},{"key":"1792_CR51","doi-asserted-by":"publisher","first-page":"208","DOI":"10.7326\/0003-4819-129-3-199808010-00009","volume":"129","author":"L Fraenkel","year":"1998","unstructured":"Fraenkel L, Zhang Y, Chaisson CE, Evans SR, Wilson PW, Felson DT (1998) The association of estrogen replacement therapy and the Raynaud phenomenon in postmenopausal women. Ann Intern Med 129:208\u2013211","journal-title":"Ann Intern Med"},{"key":"1792_CR52","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1002\/1529-0131(199902)42:2<306::AID-ANR13>3.0.CO;2-G","volume":"42","author":"L Fraenkel","year":"1999","unstructured":"Fraenkel L, Zhang Y, Chaisson CE, Maricq HR, Evans SR, Brand F, Wilson PW, Felson DT (1999) Different factors influencing the expression of Raynaud\u2019s phenomenon in men and women. Arthritis Rheum 42:306\u2013310","journal-title":"Arthritis Rheum"},{"key":"1792_CR53","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1002\/art.1780390717","volume":"39","author":"RR Freedman","year":"1996","unstructured":"Freedman RR, Mayes MD (1996) Familial aggregation of primary Raynaud\u2019s disease. Arthritis Rheum 39:1189\u20131191","journal-title":"Arthritis Rheum"},{"key":"1792_CR54","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1016\/j.jhsa.2008.11.026","volume":"34","author":"A Fregene","year":"2009","unstructured":"Fregene A, Ditmars D, Siddiqui A (2009) Botulinum toxin type A: a treatment option for digital ischemia in patients with Raynaud\u2019s phenomenon. J Hand Surg Am 34:446\u2013452","journal-title":"J Hand Surg Am"},{"key":"1792_CR55","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1007\/s00296-008-0789-z","volume":"29","author":"M Funauchi","year":"2009","unstructured":"Funauchi M, Kishimoto K, Shimazu H, Nagare Y, Hino S, Yano T, Kinoshita K (2009) Effects of bosentan on the skin lesions: an observational study from a single center in Japan. Rheumatol Int 29:769\u2013775","journal-title":"Rheumatol Int"},{"key":"1792_CR56","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2014-006389","volume":"5","author":"R Garner","year":"2015","unstructured":"Garner R, Kumari R, Lanyon P, Doherty M, Zhang W (2015) Prevalence, risk factors and associations of primary Raynaud\u2019s phenomenon: systematic review and meta-analysis of observational studies. BMJ Open 5:e006389","journal-title":"BMJ Open"},{"issue":"177\u201386","key":"1792_CR57","first-page":"x","volume":"31","author":"S Generini","year":"2005","unstructured":"Generini S, Seibold JR, Matucci-Cerinic M (2005) Estrogens and neuropeptides in Raynaud\u2019s phenomenon. Rheum Dis Clin North Am 31(177\u201386):x\u2013xi","journal-title":"Rheum Dis Clin North Am"},{"key":"1792_CR58","doi-asserted-by":"publisher","first-page":"3837","DOI":"10.1002\/art.22965","volume":"56","author":"AE Gliddon","year":"2007","unstructured":"Gliddon AE, Dore CJ, Black CM, McHugh N, Moots R, Denton CP, Herrick A, Barnes T, Camilleri J, Chakravarty K, Emery P, Griffiths B, Hopkinson ND, Hickling P, Lanyon P, Laversuch C, Lawson T, Mallya R, Nisar M, Rhys-Dillon C, Sheeran T, Maddison PJ (2007) Prevention of vascular damage in scleroderma and autoimmune Raynaud\u2019s phenomenon: a multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril. Arthritis Rheum 56:3837\u20133846","journal-title":"Arthritis Rheum"},{"key":"1792_CR59","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1097\/00043426-200411000-00017","volume":"26","author":"S Gottschling","year":"2004","unstructured":"Gottschling S, Meyer S, Reinhard H, Krenn T, Graf N (2004) First report of a vincristine dose-related Raynaud\u2019s phenomenon in an adolescent with malignant brain tumor. J Pediatr Hematol Oncol 26:768\u2013769","journal-title":"J Pediatr Hematol Oncol"},{"key":"1792_CR60","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1177\/000331979604700501","volume":"47","author":"D Greenstein","year":"1996","unstructured":"Greenstein D, Jeffcote N, Ilsley D, Kester RC (1996) The menstrual cycle and Raynaud\u2019s phenomenon. Angiology 47:427\u2013436","journal-title":"Angiology"},{"key":"1792_CR61","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1200\/JCO.1989.7.7.940","volume":"7","author":"SW Hansen","year":"1989","unstructured":"Hansen SW, Olsen N (1989) Raynaud\u2019s phenomenon in patients treated with cisplatin, vinblastine, and bleomycin for germ cell cancer: measurement of vasoconstrictor response to cold. J Clin Oncol 7:940\u2013942","journal-title":"J Clin Oncol"},{"key":"1792_CR62","doi-asserted-by":"publisher","first-page":"580","DOI":"10.7861\/clinmed.2020-0754","volume":"20","author":"A Haque","year":"2020","unstructured":"Haque A, Hughes M (2020) Raynaud\u2019s phenomenon. Clin Med (Lond) 20:580\u2013587","journal-title":"Clin Med (Lond)"},{"key":"1792_CR63","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/0895-4356(91)90026-6","volume":"44","author":"N Harada","year":"1991","unstructured":"Harada N, Ueda A, Takegata S (1991) Prevalence of Raynaud\u2019s phenomenon in Japanese males and females. J Clin Epidemiol 44:649\u2013655","journal-title":"J Clin Epidemiol"},{"key":"1792_CR64","doi-asserted-by":"publisher","first-page":"6156","DOI":"10.1038\/s41467-023-41876-5","volume":"14","author":"S Hartmann","year":"2023","unstructured":"Hartmann S, Yasmeen S, Jacobs BM, Denaxas S, Pirmohamed M, Gamazon ER, Caulfield MJ, Genes & Health Research Team, Hemingway H, Pietzner M, Langenberg C (2023) ADRA2A and IRX1 are putative risk genes for Raynaud\u2019s phenomenon. Nat Commun 14:6156","journal-title":"Nat Commun"},{"key":"1792_CR65","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1093\/rheumatology\/keh552","volume":"44","author":"AL Herrick","year":"2005","unstructured":"Herrick AL (2005) Pathogenesis of Raynaud\u2019s phenomenon. Rheumatology (Oxford) 44:587\u2013596","journal-title":"Rheumatology (Oxford)"},{"key":"1792_CR66","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1038\/nrrheum.2012.96","volume":"8","author":"AL Herrick","year":"2012","unstructured":"Herrick AL (2012) The pathogenesis, diagnosis and treatment of Raynaud phenomenon. Nat Rev Rheumatol 8:469\u2013479","journal-title":"Nat Rev Rheumatol"},{"key":"1792_CR67","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1177\/1759720X17740074","volume":"9","author":"AL Herrick","year":"2017","unstructured":"Herrick AL (2017) Evidence-based management of Raynaud\u2019s phenomenon. Ther Adv Musculoskelet Dis 9:317\u2013329","journal-title":"Ther Adv Musculoskelet Dis"},{"key":"1792_CR68","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2019.101474","volume":"34","author":"AL Herrick","year":"2020","unstructured":"Herrick AL, Wigley FM (2020) Raynaud\u2019s phenomenon. Best Pract Res Clin Rheumatol 34:101474","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"1792_CR69","first-page":"408","volume":"19","author":"A Holstein","year":"2010","unstructured":"Holstein A, Batge R, Egberts EH (2010) Gemcitabine induced digital ischaemia and necrosis. Eur J Cancer Care (Engl) 19:408\u2013409","journal-title":"Eur J Cancer Care (Engl)"},{"key":"1792_CR70","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1093\/rheumatology\/kev201","volume":"54","author":"M Hughes","year":"2015","unstructured":"Hughes M, Ong VH, Anderson ME, Hall F, Moinzadeh P, Griffiths B, Baildam E, Denton CP, Herrick AL (2015) Consensus best practice pathway of the UK Scleroderma Study Group: digital vasculopathy in systemic sclerosis. Rheumatology (Oxford) 54:2015\u20132024","journal-title":"Rheumatology (Oxford)"},{"key":"1792_CR71","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1038\/s41584-020-0386-4","volume":"16","author":"M Hughes","year":"2020","unstructured":"Hughes M, Allanore Y, Chung L, Pauling JD, Denton CP, Matucci-Cerinic M (2020) Raynaud phenomenon and digital ulcers in systemic sclerosis. Nat Rev Rheumatol 16:208\u2013221","journal-title":"Nat Rev Rheumatol"},{"key":"1792_CR72","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1097\/01720610-200611000-00006","volume":"19","author":"CM Jackson","year":"2006","unstructured":"Jackson CM (2006) The patient with cold hands: understanding Raynaud\u2019s disease. JAAPA 19:34\u201338","journal-title":"JAAPA"},{"issue":"109","key":"1792_CR73","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1152\/japplphysiol.00407.2010","volume":"1985","author":"JM Johnson","year":"2010","unstructured":"Johnson JM, Kellogg DL Jr (2010) Local thermal control of the human cutaneous circulation. J Appl Physiol 1985(109):1229\u20131238","journal-title":"J Appl Physiol"},{"key":"1792_CR74","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1093\/oxfordjournals.eurheartj.a061312","volume":"3","author":"B Kaada","year":"1982","unstructured":"Kaada B (1982) Vasodilation induced by transcutaneous nerve stimulation in peripheral ischemia (Raynaud\u2019s phenomenon and diabetic polyneuropathy). Eur Heart J 3:303\u2013314","journal-title":"Eur Heart J"},{"key":"1792_CR75","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1002\/cpdd.1018","volume":"11","author":"S Kapsa","year":"2022","unstructured":"Kapsa S, Thuss U, Boxnick S, Schaumann F, Schultz A, Unger S, Otto C (2022) Pharmacokinetics, safety, and tolerability of the alpha(2C) -adrenoreceptor antagonist BAY 1193397 in healthy male subjects. Clin Pharmacol Drug Dev 11:296\u2013308","journal-title":"Clin Pharmacol Drug Dev"},{"key":"1792_CR76","first-page":"1830","volume":"35","author":"A Kawald","year":"2008","unstructured":"Kawald A, Burmester GR, Huscher D, Sunderkotter C, Riemekasten G (2008) Low versus high-dose iloprost therapy over 21 days in patients with secondary Raynaud\u2019s phenomenon and systemic sclerosis: a randomized, open, single-center study. J Rheumatol 35:1830\u20131837","journal-title":"J Rheumatol"},{"key":"1792_CR77","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.3389\/fphys.2018.01249","volume":"9","author":"Z Kee","year":"2018","unstructured":"Kee Z, Kodji X, Brain SD (2018) The role of calcitonin gene related peptide (CGRP) in neurogenic vasodilation and its cardioprotective effects. Front Physiol 9:1249","journal-title":"Front Physiol"},{"key":"1792_CR78","unstructured":"Khan KM, Patel JB, Schaefer TJ (2025) Nifedipine. StatPearls. Treasure Island (FL) ineligible companies. Disclosure: Jayesh Patel declares no relevant financial relationships with ineligible companies. Disclosure: Timothy Schaefer declares no relevant financial relationships with ineligible companies"},{"key":"1792_CR79","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1111\/bcp.12912","volume":"82","author":"C Khouri","year":"2016","unstructured":"Khouri C, Blaise S, Carpentier P, Villier C, Cracowski JL, Roustit M (2016) Drug-induced Raynaud\u2019s phenomenon: beyond beta-adrenoceptor blockers. Br J Clin Pharmacol 82:6\u201316","journal-title":"Br J Clin Pharmacol"},{"key":"1792_CR80","doi-asserted-by":"publisher","first-page":"2307","DOI":"10.1111\/bcp.13314","volume":"83","author":"C Khouri","year":"2017","unstructured":"Khouri C, Gailland T, Lepelley M, Roustit M, Cracowski JL (2017) Fluoxetine and Raynaud\u2019s phenomenon: friend or foe? Br J Clin Pharmacol 83:2307\u20132309","journal-title":"Br J Clin Pharmacol"},{"key":"1792_CR81","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.3390\/toxins7072435","volume":"7","author":"DW Kim","year":"2015","unstructured":"Kim DW, Lee SK, Ahnn J (2015) Botulinum toxin as a pain killer: players and actions in antinociception. Toxins (Basel) 7:2435\u20132453","journal-title":"Toxins (Basel)"},{"key":"1792_CR82","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2024.103035","volume":"80","author":"J Kim","year":"2025","unstructured":"Kim J, Zhao R, Kleinberg LR, Kim K (2025) Effect of long and short half-life PDE5 inhibitors on HbA1c levels: a systematic review and meta-analysis. EClinicalMedicine 80:103035","journal-title":"EClinicalMedicine"},{"key":"1792_CR83","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1007\/s10067-014-2637-8","volume":"34","author":"A Kuryliszyn-Moskal","year":"2015","unstructured":"Kuryliszyn-Moskal A, Kita J, Dakowicz A, Chwiesko-Minarowska S, Moskal D, Kosztyla-Hojna B, Jablonska E, Klimiuk PA (2015) The influence of Multiwave Locked System (MLS) laser therapy on clinical features, microcirculatory abnormalities and selected modulators of angiogenesis in patients with Raynaud\u2019s phenomenon. Clin Rheumatol 34:489\u2013496","journal-title":"Clin Rheumatol"},{"key":"1792_CR84","volume":"13","author":"C Laboe","year":"2021","unstructured":"Laboe C, Batchelder E, Vasireddy D (2021) Persistent Raynaud\u2019s phenomenon following methylphenidate hydrochloride use during the COVID-19 pandemic. Cureus 13:e17647","journal-title":"Cureus"},{"key":"1792_CR85","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/S0013-9351(86)80070-6","volume":"39","author":"B Lagerkvist","year":"1986","unstructured":"Lagerkvist B, Linderholm H, Nordberg GF (1986) Vasospastic tendency and Raynaud\u2019s phenomenon in smelter workers exposed to arsenic. Environ Res 39:465\u2013474","journal-title":"Environ Res"},{"key":"1792_CR86","doi-asserted-by":"publisher","first-page":"2174","DOI":"10.1097\/CCM.0b013e31817d1a92","volume":"36","author":"T Lahm","year":"2008","unstructured":"Lahm T, Crisostomo PR, Markel TA, Wang M, Weil BR, Novotny NM, Meldrum DR (2008) The effects of estrogen on pulmonary artery vasoreactivity and hypoxic pulmonary vasoconstriction: potential new clinical implications for an old hormone. Crit Care Med 36:2174\u20132183","journal-title":"Crit Care Med"},{"key":"1792_CR87","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1016\/j.jvs.2013.03.012","volume":"57","author":"GJ Landry","year":"2013","unstructured":"Landry GJ (2013) Current medical and surgical management of Raynaud\u2019s syndrome. J Vasc Surg 57:1710\u20131716","journal-title":"J Vasc Surg"},{"key":"1792_CR88","doi-asserted-by":"publisher","first-page":"616","DOI":"10.3899\/jrheum.200716","volume":"48","author":"D Langleben","year":"2021","unstructured":"Langleben D, Berkson L, Chartrand S (2021) Selexipag therapy for Raynaud phenomenon-induced severe digital ischemia in intravenous epoprostenol responders with connective tissue disease. J Rheumatol 48:616\u2013617","journal-title":"J Rheumatol"},{"key":"1792_CR89","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1093\/rheumatology\/ket417","volume":"53","author":"EY Lee","year":"2014","unstructured":"Lee EY, Park JK, Lee W, Kim YK, Park CS, Giles JT, Park JW, Shin K, Lee JS, Song YW, Lee EB (2014) Head-to-head comparison of udenafil vs amlodipine in the treatment of secondary Raynaud\u2019s phenomenon: a double-blind, randomized, cross-over study. Rheumatology (Oxford) 53:658\u2013664","journal-title":"Rheumatology (Oxford)"},{"key":"1792_CR90","doi-asserted-by":"publisher","first-page":"H1105","DOI":"10.1152\/ajpheart.00645.2013","volume":"306","author":"T Li","year":"2014","unstructured":"Li T, Xiao X, Zhang J, Zhu Y, Hu Y, Zang J, Lu K, Yang T, Ge H, Peng X, Lan D, Liu L (2014) Age and sex differences in vascular responsiveness in healthy and trauma patients: contribution of estrogen receptor-mediated Rho kinase and PKC pathways. Am J Physiol Heart Circ Physiol 306:H1105\u2013H1115","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"1792_CR91","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1016\/S0140-6736(05)60005-0","volume":"352","author":"D Linden","year":"1998","unstructured":"Linden D (1998) Severe Raynaud\u2019s phenomenon associated with interferon-beta treatment for multiple sclerosis. Lancet 352:878\u2013879","journal-title":"Lancet"},{"key":"1792_CR92","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1024\/0301-1526\/a000526","volume":"45","author":"B Linnemann","year":"2016","unstructured":"Linnemann B, Erbe M (2016) Raynaud\u2019s phenomenon and digital ischaemia\u2013pharmacologic approach and alternative treatment options. Vasa 45:201\u2013212","journal-title":"Vasa"},{"key":"1792_CR93","doi-asserted-by":"publisher","first-page":"e002785","DOI":"10.1136\/bmjopen-2013-002785","volume":"3","author":"V Lopez","year":"2013","unstructured":"Lopez V, Chamoux A, Tempier M, Thiel H, Ughetto S, Trousselard M, Naughton G, Dutheil F (2013) The long-term effects of occupational exposure to vinyl chloride monomer on microcirculation: a cross-sectional study 15 years after retirement. BMJ Open 3:e002785","journal-title":"BMJ Open"},{"key":"1792_CR94","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1113\/jphysiol.1993.sp019491","volume":"460","author":"K Lossius","year":"1993","unstructured":"Lossius K, Eriksen M, Walloe L (1993) Fluctuations in blood flow to acral skin in humans: connection with heart rate and blood pressure variability. J Physiol 460:641\u2013655","journal-title":"J Physiol"},{"key":"1792_CR95","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/S0165-6147(97)90625-8","volume":"18","author":"E MacDonald","year":"1997","unstructured":"MacDonald E, Kobilka BK, Scheinin M (1997) Gene targeting\u2013homing in on alpha 2-adrenoceptor-subtype function. Trends Pharmacol Sci 18:211\u2013219","journal-title":"Trends Pharmacol Sci"},{"key":"1792_CR96","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1093\/rheumatology\/41.9.965","volume":"41","author":"P Maddison","year":"2002","unstructured":"Maddison P (2002) Prevention of vascular damage in scleroderma with angiotensin-converting enzyme (ACE) inhibition. Rheumatology (Oxford) 41:965\u2013971","journal-title":"Rheumatology (Oxford)"},{"key":"1792_CR97","first-page":"879","volume":"24","author":"HR Maricq","year":"1997","unstructured":"Maricq HR, Carpentier PH, Weinrich MC, Keil JE, Palesch Y, Biro C, Vionnet-Fuasset M, Jiguet M, Valter I (1997) Geographic variation in the prevalence of Raynaud\u2019s phenomenon: a 5 region comparison. J Rheumatol 24:879\u2013889","journal-title":"J Rheumatol"},{"key":"1792_CR98","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.jaut.2014.01.020","volume":"48\u201349","author":"E Maverakis","year":"2014","unstructured":"Maverakis E, Patel F, Kronenberg DG, Chung L, Fiorentino D, Allanore Y, Guiducci S, Hesselstrand R, Hummers LK, Duong C, Kahaleh B, MacGregor A, Matucci-Cerinic M, Wollheim FA, Mayes MD, Gershwin ME (2014) International consensus criteria for the diagnosis of Raynaud\u2019s phenomenon. J Autoimmun 48\u201349:60\u201365","journal-title":"J Autoimmun"},{"key":"1792_CR99","doi-asserted-by":"publisher","first-page":"224","DOI":"10.5152\/eurjrheum.2018.18013","volume":"5","author":"S Medina","year":"2018","unstructured":"Medina S, Gomez-Zubiaur A, Valdeolivas-Casillas N, Polo-Rodriguez I, Ruiz L, Izquierdo C, Guirado C, Cabrera A, Trasobares L (2018) Botulinum toxin type A in the treatment of Raynaud\u2019s phenomenon: a three-year follow-up study. Eur J Rheumatol 5:224\u2013229","journal-title":"Eur J Rheumatol"},{"key":"1792_CR100","first-page":"209","volume":"41","author":"GC Mereto","year":"1975","unstructured":"Mereto GC, Balestra L, Aliotta P (1975) Problems of resuscitation in poisoning. Acute heroin poisoning. Minerva Anestesiol 41:209\u2013217","journal-title":"Minerva Anestesiol"},{"key":"1792_CR101","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1093\/rheumatology\/kel038","volume":"45","author":"G Milio","year":"2006","unstructured":"Milio G, Corrado E, Genova C, Amato C, Raimondi F, Almasio PL, Novo S (2006) Iloprost treatment in patients with Raynaud\u2019s phenomenon secondary to systemic sclerosis and the quality of life: a new therapeutic protocol. Rheumatology (Oxford) 45:999\u20131004","journal-title":"Rheumatology (Oxford)"},{"key":"1792_CR102","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1111\/j.1440-1681.1995.tb01938.x","volume":"22","author":"JL Morris","year":"1995","unstructured":"Morris JL (1995) Peptides as neurotransmitters in vascular autonomic neurons. Clin Exp Pharmacol Physiol 22:792\u2013802","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"1792_CR103","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1191\/1358863x02vm455oa","volume":"7","author":"AH Muir","year":"2002","unstructured":"Muir AH, Robb R, McLaren M, Daly F, Belch JJ (2002) The use of Ginkgo biloba in Raynaud\u2019s disease: a double-blind placebo-controlled trial. Vasc Med 7:265\u2013267","journal-title":"Vasc Med"},{"key":"1792_CR104","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0196279","volume":"13","author":"S Munir","year":"2018","unstructured":"Munir S, Freidin MB, Brain S, Williams FMK (2018) Association of Raynaud\u2019s phenomenon with a polymorphism in the NOS1 gene. PLoS ONE 13:e0196279","journal-title":"PLoS ONE"},{"key":"1792_CR105","volume":"14","author":"I Nawaz","year":"2022","unstructured":"Nawaz I, Nawaz Y, Nawaz E, Manan MR, Mahmood A (2022) Raynaud\u2019s phenomenon: reviewing the pathophysiology and management strategies. Cureus 14:e21681","journal-title":"Cureus"},{"key":"1792_CR106","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1097\/PRS.0b013e3181a80576","volume":"124","author":"MW Neumeister","year":"2009","unstructured":"Neumeister MW, Chambers CB, Herron MS, Webb K, Wietfeldt J, Gillespie JN, Bueno RA Jr, Cooney CM (2009) Botox therapy for ischemic digits. Plast Reconstr Surg 124:191\u2013201","journal-title":"Plast Reconstr Surg"},{"key":"1792_CR107","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1093\/rheumatology\/kep413","volume":"49","author":"VA Nguyen","year":"2010","unstructured":"Nguyen VA, Eisendle K, Gruber I, Hugl B, Reider D, Reider N (2010) Effect of the dual endothelin receptor antagonist bosentan on Raynaud\u2019s phenomenon secondary to systemic sclerosis: a double-blind prospective, randomized, placebo-controlled pilot study. Rheumatology (Oxford) 49:583\u2013587","journal-title":"Rheumatology (Oxford)"},{"key":"1792_CR108","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1067\/mvn.2001.117786","volume":"19","author":"CM O\u2019Connor","year":"2001","unstructured":"O\u2019Connor CM (2001) Raynaud\u2019s phenomenon. J Vasc Nurs 19:87\u201392","journal-title":"J Vasc Nurs"},{"key":"1792_CR109","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1136\/bmj.294.6581.1186","volume":"294","author":"N Olsen","year":"1987","unstructured":"Olsen N, Petring OU, Rossing N (1987) Exaggerated postural vasoconstrictor reflex in Raynaud\u2019s phenomenon. Br Med J (Clin Res Ed) 294:1186\u20131188","journal-title":"Br Med J (Clin Res Ed)"},{"key":"1792_CR110","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1136\/ard.2003.006338","volume":"63","author":"T Oskay","year":"2004","unstructured":"Oskay T, Olmez U (2004) Primary Raynaud\u2019s phenomenon in monozygotic twins. Ann Rheum Dis 63:219","journal-title":"Ann Rheum Dis"},{"key":"1792_CR111","doi-asserted-by":"publisher","first-page":"3317","DOI":"10.1007\/s10067-019-04745-5","volume":"38","author":"JD Pauling","year":"2019","unstructured":"Pauling JD, Hughes M, Pope JE (2019) Raynaud\u2019s phenomenon-an update on diagnosis, classification and management. Clin Rheumatol 38:3317\u20133330","journal-title":"Clin Rheumatol"},{"key":"1792_CR112","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0103099","volume":"9","author":"M Pawlowski","year":"2014","unstructured":"Pawlowski M, Saraswathi S, Motawea HK, Chotani MA, Kloczkowski A (2014) In silico modeling of human alpha2C-adrenoreceptor interaction with filamin-2. PLoS ONE 9:e103099","journal-title":"PLoS ONE"},{"key":"1792_CR113","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.jaad.2024.09.034","volume":"92","author":"EL Pinto-Pulido","year":"2025","unstructured":"Pinto-Pulido EL, Polo-Rodriguez I, Garcia-Verdu E, Merlo-Gomez P, Martinez-Alcalde L, Ruiz-Gutierrez L, Medina-Montalvo S (2025) Botulinum toxin for Raynaud\u2019s phenomenon: a decade of real-world evidence. J Am Acad Dermatol 92:173\u2013175","journal-title":"J Am Acad Dermatol"},{"key":"1792_CR114","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/S0398-0499(06)76512-X","volume":"31","author":"MA Pistorius","year":"2006","unstructured":"Pistorius MA, Planchon B, Schott JJ, Lemarec H (2006) Heredity and genetic aspects of Raynaud\u2019s disease. J Mal Vasc 31:10\u201315","journal-title":"J Mal Vasc"},{"key":"1792_CR115","first-page":"467","volume":"34","author":"P Plissonneau Duquene","year":"2015","unstructured":"Plissonneau Duquene P, Pistorius MA, Pottier P, Aymard B, Planchon B (2015) Cold climate could be an etiologic factor involved in Raynaud\u2019s phenomenon physiopathology. epidemiological investigation from 954 consultations in general practice. Int Angiol 34:467\u2013474","journal-title":"Int Angiol"},{"key":"1792_CR116","first-page":"117","volume":"35","author":"P Poredos","year":"2016","unstructured":"Poredos P, Poredos P (2016) Raynaud\u2019s syndrome: a neglected disease. Int Angiol 35:117\u2013121","journal-title":"Int Angiol"},{"key":"1792_CR117","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.autrev.2013.12.001","volume":"13","author":"M Prete","year":"2014","unstructured":"Prete M, Fatone MC, Favoino E, Perosa F (2014) Raynaud\u2019s phenomenon: from molecular pathogenesis to therapy. Autoimmun Rev 13:655\u2013667","journal-title":"Autoimmun Rev"},{"key":"1792_CR118","first-page":"CD000467","volume":"12","author":"F Rirash","year":"2017","unstructured":"Rirash F, Tingey PC, Harding SE, Maxwell LJ, Tanjong Ghogomu E, Wells GA, Tugwell P, Pope J (2017) Calcium channel blockers for primary and secondary Raynaud\u2019s phenomenon. Cochrane Database Syst Rev 12:CD000467","journal-title":"Cochrane Database Syst Rev"},{"key":"1792_CR119","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1007\/s100670170076","volume":"20","author":"JA Roman Ivorra","year":"2001","unstructured":"Roman Ivorra JA, Gonzalvez Perales JL, Fernandez Carballido C, Grana J, Torres MJ (2001) Prevalence of Raynaud\u2019s phenomenon in general practice in the east of Spain. Clin Rheumatol 20:88\u201390","journal-title":"Clin Rheumatol"},{"key":"1792_CR120","doi-asserted-by":"publisher","first-page":"115","DOI":"10.2515\/therapie\/2013068","volume":"69","author":"M Roustit","year":"2014","unstructured":"Roustit M, Khouri C, Blaise S, Villier C, Carpentier P, Cracowski JL (2014) Pharmacology of Raynaud\u2019s phenomenon. Therapie 69:115\u2013128","journal-title":"Therapie"},{"key":"1792_CR121","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1159\/000247759","volume":"182","author":"J Saban","year":"1991","unstructured":"Saban J, Rodriguez-Garcia JL, Pais JR, Mellado N, Munoz E (1991) Raynaud\u2019s phenomenon with digital necrosis as the first manifestation of undifferentiated connective tissue syndrome. Dermatologica 182:121\u2013123","journal-title":"Dermatologica"},{"key":"1792_CR122","volume":"8","author":"MW Saif","year":"2016","unstructured":"Saif MW, Agarwal A, Hellinger J, Park DJ, Volkmann E (2016) Scleroderma in a patient on capecitabine: is this a variant of hand-foot syndrome? Cureus 8:e663","journal-title":"Cureus"},{"key":"1792_CR123","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1124\/mol.51.1.36","volume":"51","author":"J Sallinen","year":"1997","unstructured":"Sallinen J, Link RE, Haapalinna A, Viitamaa T, Kulatunga M, Sjoholm B, MacDonald E, Pelto-Huikko M, Leino T, Barsh GS, Kobilka BK, Scheinin M (1997) Genetic alteration of alpha 2C-adrenoceptor expression in mice: influence on locomotor, hypothermic, and neurochemical effects of dexmedetomidine, a subtype-nonselective alpha 2-adrenoceptor agonist. Mol Pharmacol 51:36\u201346","journal-title":"Mol Pharmacol"},{"key":"1792_CR124","first-page":"503","volume":"19","author":"R Scorza","year":"2001","unstructured":"Scorza R, Caronni M, Mascagni B, Berruti V, Bazzi S, Micallef E, Arpaia G, Sardina M, Origgi L, Vanoli M (2001) Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud\u2019s phenomenon. A randomized, controlled study. Clin Exp Rheumatol 19:503\u2013508","journal-title":"Clin Exp Rheumatol"},{"issue":"Suppl 3","key":"1792_CR125","first-page":"iii45","volume":"45","author":"N Selenko-Gebauer","year":"2006","unstructured":"Selenko-Gebauer N, Duschek N, Minimair G, Stingl G, Karlhofer F (2006) Successful treatment of patients with severe secondary Raynaud\u2019s phenomenon with the endothelin receptor antagonist bosentan. Rheumatology (Oxford) 45(Suppl 3):iii45\u2013iii48","journal-title":"Rheumatology (Oxford)"},{"key":"1792_CR126","doi-asserted-by":"publisher","first-page":"S119","DOI":"10.1097\/00002508-200211001-00002","volume":"18","author":"PE Setler","year":"2002","unstructured":"Setler PE (2002) Therapeutic use of botulinum toxins: background and history. Clin J Pain 18:S119\u2013S124","journal-title":"Clin J Pain"},{"key":"1792_CR127","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1177\/000331977602700104","volume":"27","author":"BP Shagan","year":"1976","unstructured":"Shagan BP, Friedman SA (1976) Raynaud\u2019s phenomenon in hypothyroidism. Angiology 27:19\u201325","journal-title":"Angiology"},{"key":"1792_CR128","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1001\/archinte.1980.00330180106029","volume":"140","author":"BP Shagan","year":"1980","unstructured":"Shagan BP, Friedman SA (1980) Raynaud\u2019s phenomenon and thyroid deficiency. Arch Intern Med 140:832\u2013833","journal-title":"Arch Intern Med"},{"key":"1792_CR129","first-page":"213","volume":"1","author":"D Sorriento","year":"2011","unstructured":"Sorriento D, Trimarco B, Iaccarino G (2011) Adrenergic mechanism in the control of endothelial function. Transl Med UniSa 1:213\u2013228","journal-title":"Transl Med UniSa"},{"key":"1792_CR130","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/j.jhsa.2012.01.021","volume":"37","author":"AV Stone","year":"2012","unstructured":"Stone AV, Koman LA, Callahan MF, Eckman DM, Smith BP, Plate JF, Smith TL (2012) The effect of botulinum neurotoxin-A on blood flow in rats: a potential mechanism for treatment of Raynaud phenomenon. J Hand Surg Am 37:795\u2013802","journal-title":"J Hand Surg Am"},{"key":"1792_CR131","doi-asserted-by":"publisher","first-page":"1641","DOI":"10.1002\/1529-0131(200007)43:7<1641::AID-ANR30>3.0.CO;2-Y","volume":"43","author":"E Susol","year":"2000","unstructured":"Susol E, Macgregor AJ, Barrett JH, Wilson H, Black C, Welsh K, Silman A, Ollier B, Worthington J (2000) A two-stage, genome-wide screen for susceptibility loci in primary Raynaud\u2019s phenomenon. Arthritis Rheum 43:1641\u20131646","journal-title":"Arthritis Rheum"},{"key":"1792_CR132","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1111\/j.1365-2362.2004.01324.x","volume":"34","author":"T Sycha","year":"2004","unstructured":"Sycha T, Graninger M, Auff E, Schnider P (2004) Botulinum toxin in the treatment of Raynaud\u2019s phenomenon: a pilot study. Eur J Clin Invest 34:312\u2013313","journal-title":"Eur J Clin Invest"},{"key":"1792_CR133","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1097\/00002281-200011000-00007","volume":"12","author":"FK Tan","year":"2000","unstructured":"Tan FK, Arnett FC (2000) Genetic factors in the etiology of systemic sclerosis and Raynaud phenomenon. Curr Opin Rheumatol 12:511\u2013519","journal-title":"Curr Opin Rheumatol"},{"key":"1792_CR134","first-page":"123","volume":"113","author":"KK Temprano","year":"2016","unstructured":"Temprano KK (2016) A review of Raynaud\u2019s disease. Mo Med 113:123\u2013126","journal-title":"Mo Med"},{"key":"1792_CR135","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1093\/rheumatology\/keh390","volume":"44","author":"AE Thompson","year":"2005","unstructured":"Thompson AE, Pope JE (2005) Calcium channel blockers for primary Raynaud\u2019s phenomenon: a meta-analysis. Rheumatology (Oxford) 44:145\u2013150","journal-title":"Rheumatology (Oxford)"},{"key":"1792_CR136","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1097\/01.prs.0000244860.00674.57","volume":"119","author":"AL Van Beek","year":"2007","unstructured":"Van Beek AL, Lim PK, Gear AJL, Pritzker MR (2007) Management of vasospastic disorders with botulinum toxin A. Plast Reconstr Surg 119:217\u2013226","journal-title":"Plast Reconstr Surg"},{"key":"1792_CR137","doi-asserted-by":"publisher","first-page":"2737","DOI":"10.1002\/art.38098","volume":"65","author":"F Van Den Hoogen","year":"2013","unstructured":"Van Den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, Van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Muller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE (2013) 2013 classification criteria for systemic sclerosis: an American College of Rheumatology\/European League against Rheumatism collaborative initiative. Arthritis Rheum 65:2737\u20132747","journal-title":"Arthritis Rheum"},{"key":"1792_CR138","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1097\/00001813-200311000-00009","volume":"14","author":"L Venat-Bouvet","year":"2003","unstructured":"Venat-Bouvet L, Ly K, Szelag JC, Martin J, Labourey JL, Genet D, Tubiana-Mathieu N (2003) Thrombotic microangiopathy and digital necrosis: two unrecognized toxicities of gemcitabine. Anticancer Drugs 14:829\u2013832","journal-title":"Anticancer Drugs"},{"key":"1792_CR139","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1080\/23328940.2015.1088502","volume":"3","author":"L Walloe","year":"2016","unstructured":"Walloe L (2016) Arterio-venous anastomoses in the human skin and their role in temperature control. Temperature (Austin) 3:92\u2013103","journal-title":"Temperature (Austin)"},{"key":"1792_CR140","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1113\/jphysiol.2003.059899","volume":"555","author":"CR White","year":"2004","unstructured":"White CR, Haidekker MA, Stevens HY, Frangos JA (2004) Extracellular signal-regulated kinase activation and endothelin-1 production in human endothelial cells exposed to vibration. J Physiol 555:565\u2013572","journal-title":"J Physiol"},{"key":"1792_CR141","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1056\/NEJMcp013013","volume":"347","author":"FM Wigley","year":"2002","unstructured":"Wigley FM (2002) Clinical practice. Raynaud\u2019s phenomenon. N Engl J Med 347:1001\u20131008","journal-title":"N Engl J Med"},{"key":"1792_CR142","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1056\/NEJMra1507638","volume":"375","author":"FM Wigley","year":"2016","unstructured":"Wigley FM, Flavahan NA (2016) Raynaud\u2019s phenomenon. N Engl J Med 375:556\u2013565","journal-title":"N Engl J Med"},{"key":"1792_CR143","first-page":"492","volume":"31","author":"YJ Wu","year":"2008","unstructured":"Wu YJ, Luo SF, Yang SH, Chen JY, Yu KH, See LC (2008) Vascular response of Raynaud\u2019s phenomenon to nifedipine or herbal medication (duhuo-tisheng tang with danggui-sini tang): a preliminary study. Chang Gung Med J 31:492\u2013502","journal-title":"Chang Gung Med J"},{"key":"1792_CR144","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000002575","volume":"95","author":"H Zhang","year":"2016","unstructured":"Zhang H, Li X, Huang J, Li H, Su Z, Wang J (2016) Comparative efficacy and safety of prostacyclin analogs for pulmonary arterial hypertension: a network meta-analysis. Medicine (Baltimore) 95:e2575","journal-title":"Medicine (Baltimore)"},{"key":"1792_CR145","first-page":"509","volume":"40","author":"J Zhang","year":"2020","unstructured":"Zhang J, Hu J, He X, Meng Y, Chen G, Chen Z, Lu J, Li P (2020) Effectiveness of Chinese herbal medicine for primary Raynaud\u2019s phenomenon: a systematic review and Meta-analysis of randomized controlled trials. J Tradit Chin Med 40:509\u2013517","journal-title":"J Tradit Chin Med"}],"container-title":["Inflammopharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10787-025-01792-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10787-025-01792-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10787-025-01792-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T19:43:49Z","timestamp":1757187829000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10787-025-01792-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,12]]},"references-count":145,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["1792"],"URL":"https:\/\/doi.org\/10.1007\/s10787-025-01792-0","relation":{},"ISSN":["0925-4692","1568-5608"],"issn-type":[{"value":"0925-4692","type":"print"},{"value":"1568-5608","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,12]]},"assertion":[{"value":"9 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 June 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}