{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:08:11Z","timestamp":1788343691274,"version":"build-2803163510"},"reference-count":31,"publisher":"National Academy of Sciences","issue":"26","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>Curative treatment modalities for erectile dysfunction (ED) are not available. Penile erection is a neurovascular phenomenon, and ED is caused mainly by vascular and neurologic disturbances. Here we demonstrate that inhibition of nerve injury-induced protein 1 promotes penile angiogenesis and neural regeneration through angiopoietin-1\u2013Tie2 signaling and rescues erectile function in diabetic mice. Our preclinical work shed light on the application of therapeutic angiogenesis and neural regeneration for the treatment of human ED.<\/jats:p>","DOI":"10.1073\/pnas.1403471111","type":"journal-article","created":{"date-parts":[[2014,6,16]],"date-time":"2014-06-16T22:56:38Z","timestamp":1402959398000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":63,"title":["Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse"],"prefix":"10.1073","volume":"111","author":[{"given":"Guo Nan","family":"Yin","sequence":"first","affiliation":[{"name":"National Research Center for Sexual Medicine and"},{"name":"Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Ji","family":"Choi","sequence":"additional","affiliation":[{"name":"National Research Center for Sexual Medicine and"},{"name":"Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo Jean","family":"Kim","sequence":"additional","affiliation":[{"name":"National Research Center for Sexual Medicine and"},{"name":"Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Hye","family":"Kwon","sequence":"additional","affiliation":[{"name":"National Research Center for Sexual Medicine and"},{"name":"Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang-Moon","family":"Song","sequence":"additional","affiliation":[{"name":"National Research Center for Sexual Medicine and"},{"name":"Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Mi","family":"Park","sequence":"additional","affiliation":[{"name":"National Research Center for Sexual Medicine and"},{"name":"Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nando Dulal","family":"Das","sequence":"additional","affiliation":[{"name":"National Research Center for Sexual Medicine and"},{"name":"Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki-Dong","family":"Kwon","sequence":"additional","affiliation":[{"name":"National Research Center for Sexual Medicine and"},{"name":"Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dulguun","family":"Batbold","sequence":"additional","affiliation":[{"name":"National Research Center for Sexual Medicine and"},{"name":"Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goo Taeg","family":"Oh","sequence":"additional","affiliation":[{"name":"Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gou Young","family":"Koh","sequence":"additional","affiliation":[{"name":"National Research Laboratory of Vascular Biology and Stem Cells and"},{"name":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyu-Won","family":"Kim","sequence":"additional","affiliation":[{"name":"Neurovascular Coordination Research Center, College of Pharmacy and"},{"name":"Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Kan","family":"Ryu","sequence":"additional","affiliation":[{"name":"National Research Center for Sexual Medicine and"},{"name":"Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Kyu","family":"Suh","sequence":"additional","affiliation":[{"name":"National Research Center for Sexual Medicine and"},{"name":"Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2014,6,16]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","unstructured":"National Institutes of Health Consensus Development Panel on Impotence (1993) Impotence. NIH Consensus Conference. JAMA 270(1):83\u201390.","DOI":"10.1001\/jama.270.1.83"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.amjcard.2009.05.002","article-title":"The American Journal of Cardiology and Journal of Periodontology Editors\u2019 Consensus: Periodontitis and atherosclerotic cardiovascular disease","volume":"104","author":"Friedewald VE","year":"2009","unstructured":"VE Friedewald, et al., The American Journal of Cardiology and Journal of Periodontology Editors\u2019 Consensus: Periodontitis and atherosclerotic cardiovascular disease. Am J Cardiol; American Journal of Cardiology; Journal of Periodontology 104, 59\u201368 (2009).","journal-title":"Am J Cardiol"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1056\/NEJM200006153422407","article-title":"Erectile dysfunction","volume":"342","author":"Lue TF","year":"2000","unstructured":"TF Lue, Erectile dysfunction. N Engl J Med 342, 1802\u20131813 (2000).","journal-title":"N Engl J Med"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S0889-8529(05)70329-7","article-title":"Diabetic sexual dysfunction","volume":"25","author":"Hakim LS","year":"1996","unstructured":"LS Hakim, I Goldstein, Diabetic sexual dysfunction. Endocrinol Metab Clin North Am 25, 379\u2013400 (1996).","journal-title":"Endocrinol Metab Clin North Am"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1111\/j.1743-6109.2008.01168.x","article-title":"Erectile dysfunction in diabetes mellitus","volume":"6","author":"Malavige LS","year":"2009","unstructured":"LS Malavige, JC Levy, Erectile dysfunction in diabetes mellitus. J Sex Med 6, 1232\u20131247 (2009).","journal-title":"J Sex Med"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1111\/j.1743-6109.2007.00440.x","article-title":"Testosterone regulates RhoA\/Rho-kinase signaling in two distinct animal models of chemical diabetes","volume":"4","author":"Vignozzi L","year":"2007","unstructured":"L Vignozzi, et al., Testosterone regulates RhoA\/Rho-kinase signaling in two distinct animal models of chemical diabetes. J Sex Med 4, 620\u2013630, discussion 631\u2013632 (2007).","journal-title":"J Sex Med"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1159\/000049850","article-title":"Prognostic factors for response to sildenafil in patients with erectile dysfunction","volume":"40","author":"Mart\u00ednez-Jabaloyas JM","year":"2001","unstructured":"JM Mart\u00ednez-Jabaloyas, et al., Prognostic factors for response to sildenafil in patients with erectile dysfunction. Eur Urol 40, 641\u2013646, discussion 647 (2001).","journal-title":"Eur Urol"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/sj.ijir.3901494","article-title":"Endothelial dysfunction in diabetic erectile dysfunction","volume":"19","author":"Musicki B","year":"2007","unstructured":"B Musicki, AL Burnett, Endothelial dysfunction in diabetic erectile dysfunction. Int J Impot Res 19, 129\u2013138 (2007).","journal-title":"Int J Impot Res"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1111\/j.1743-6109.2009.01587.x","article-title":"Diabetes exacerbates the functional deficiency of NO\/cGMP pathway associated with erectile dysfunction in human corpus cavernosum and penile arteries","volume":"7","author":"Angulo J","year":"2010","unstructured":"J Angulo, et al., Diabetes exacerbates the functional deficiency of NO\/cGMP pathway associated with erectile dysfunction in human corpus cavernosum and penile arteries. J Sex Med 7, 758\u2013768 (2010).","journal-title":"J Sex Med"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/S0092-8674(00)81812-7","article-title":"Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning","volume":"87","author":"Davis S","year":"1996","unstructured":"S Davis, et al., Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87, 1161\u20131169 (1996).","journal-title":"Cell"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1006\/scdb.2001.0288","article-title":"The angiopoietins and Tie2\/Tek: Adding to the complexity of cardiovascular development","volume":"13","author":"Ward NL","year":"2002","unstructured":"NL Ward, DJ Dumont, The angiopoietins and Tie2\/Tek: Adding to the complexity of cardiovascular development. Semin Cell Dev Biol 13, 19\u201327 (2002).","journal-title":"Semin Cell Dev Biol"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/S0092-8674(00)81813-9","article-title":"Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis","volume":"87","author":"Suri C","year":"1996","unstructured":"C Suri, et al., Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87, 1171\u20131180 (1996).","journal-title":"Cell"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"2912","DOI":"10.1111\/jsm.12278","article-title":"Effect of intracavernous administration of angiopoietin-4 on erectile function in the streptozotocin-induced diabetic mouse","volume":"10","author":"Kwon MH","year":"2013","unstructured":"MH Kwon, et al., Effect of intracavernous administration of angiopoietin-4 on erectile function in the streptozotocin-induced diabetic mouse. J Sex Med 10, 2912\u20132927 (2013).","journal-title":"J Sex Med"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"969","DOI":"10.2337\/db10-0354","article-title":"Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse","volume":"60","author":"Jin HR","year":"2011","unstructured":"HR Jin, et al., Intracavernous delivery of a designed angiopoietin-1 variant rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse. Diabetes 60, 969\u2013980 (2011).","journal-title":"Diabetes"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"3635","DOI":"10.1111\/j.1743-6109.2010.01925.x","article-title":"Intracavernous delivery of synthetic angiopoietin-1 protein as a novel therapeutic strategy for erectile dysfunction in the type II diabetic db\/db mouse","volume":"7","author":"Jin HR","year":"2010","unstructured":"HR Jin, et al., Intracavernous delivery of synthetic angiopoietin-1 protein as a novel therapeutic strategy for erectile dysfunction in the type II diabetic db\/db mouse. J Sex Med 7, 3635\u20133646 (2010).","journal-title":"J Sex Med"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1097\/01.ju.0000158056.66236.1f","article-title":"Improvement in erectile dysfunction after neurotrophic factor gene therapy in diabetic rats","volume":"173","author":"Bennett NE","year":"2005","unstructured":"NE Bennett, et al., Improvement in erectile dysfunction after neurotrophic factor gene therapy in diabetic rats. J Urol 173, 1820\u20131824 (2005).","journal-title":"J Urol"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/S0896-6273(00)80166-X","article-title":"Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth","volume":"17","author":"Araki T","year":"1996","unstructured":"T Araki, J Milbrandt, Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth. Neuron 17, 353\u2013361 (1996).","journal-title":"Neuron"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1002\/ana.22519","article-title":"Role of Ninjurin-1 in the migration of myeloid cells to central nervous system inflammatory lesions","volume":"70","author":"Ifergan I","year":"2011","unstructured":"I Ifergan, et al., Role of Ninjurin-1 in the migration of myeloid cells to central nervous system inflammatory lesions. Ann Neurol 70, 751\u2013763 (2011).","journal-title":"Ann Neurol"},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1038\/cdd.2009.78","article-title":"Ninjurin1 mediates macrophage-induced programmed cell death during early ocular development","volume":"16","author":"Lee HJ","year":"2009","unstructured":"HJ Lee, et al., Ninjurin1 mediates macrophage-induced programmed cell death during early ocular development. Cell Death Differ 16, 1395\u20131407 (2009).","journal-title":"Cell Death Differ"},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.1111\/j.1743-6109.2009.01464.x","article-title":"Functional and morphologic characterizations of the diabetic mouse corpus cavernosum: Comparison of a multiple low-dose and a single high-dose streptozotocin protocols","volume":"6","author":"Jin HR","year":"2009","unstructured":"HR Jin, et al., Functional and morphologic characterizations of the diabetic mouse corpus cavernosum: Comparison of a multiple low-dose and a single high-dose streptozotocin protocols. J Sex Med 6, 3289\u20133304 (2009).","journal-title":"J Sex Med"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"2318","DOI":"10.1111\/j.1743-6109.2008.00977.x","article-title":"Role of increased penile expression of transforming growth factor-beta1 and activation of the Smad signaling pathway in erectile dysfunction in streptozotocin-induced diabetic rats","volume":"5","author":"Zhang LW","year":"2008","unstructured":"LW Zhang, et al., Role of increased penile expression of transforming growth factor-beta1 and activation of the Smad signaling pathway in erectile dysfunction in streptozotocin-induced diabetic rats. J Sex Med 5, 2318\u20132329 (2008).","journal-title":"J Sex Med"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1016\/S0022-5347(05)67111-X","article-title":"Reduction of endothelial and smooth muscle density in the corpora cavernosa of the streptozotocin induced diabetic rat","volume":"164","author":"Burchardt T","year":"2000","unstructured":"T Burchardt, et al., Reduction of endothelial and smooth muscle density in the corpora cavernosa of the streptozotocin induced diabetic rat. J Urol 164, 1807\u20131811 (2000).","journal-title":"J Urol"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/nrm2639","article-title":"Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system","volume":"10","author":"Augustin HG","year":"2009","unstructured":"HG Augustin, GY Koh, G Thurston, K Alitalo, Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10, 165\u2013177 (2009).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1161\/01.RES.86.1.24","article-title":"Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3\u2032-Kinase\/Akt signal transduction pathway","volume":"86","author":"Kim I","year":"2000","unstructured":"I Kim, et al., Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3\u2032-Kinase\/Akt signal transduction pathway. Circ Res 86, 24\u201329 (2000).","journal-title":"Circ Res"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"9102","DOI":"10.1074\/jbc.275.13.9102","article-title":"Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt\/survivin pathway","volume":"275","author":"Papapetropoulos A","year":"2000","unstructured":"A Papapetropoulos, et al., Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt\/survivin pathway. J Biol Chem 275, 9102\u20139105 (2000).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1080\/10623320214733","article-title":"The role of hydrogen peroxide in endothelial proliferative responses","volume":"9","author":"Stone JR","year":"2002","unstructured":"JR Stone, T Collins, The role of hydrogen peroxide in endothelial proliferative responses. Endothelium 9, 231\u2013238 (2002).","journal-title":"Endothelium"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.cellbi.2004.03.004","article-title":"Low concentration of oxidant and nitric oxide donors stimulate proliferation of human endothelial cells in vitro","volume":"28","author":"\u0141uczak K","year":"2004","unstructured":"K \u0141uczak, A Balcerczyk, M Soszy\u0144ski, G Bartosz, Low concentration of oxidant and nitric oxide donors stimulate proliferation of human endothelial cells in vitro. Cell Biol Int 28, 483\u2013486 (2004).","journal-title":"Cell Biol Int"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1161\/01.RES.86.5.494","article-title":"NAD(P)H oxidase: Role in cardiovascular biology and disease","volume":"86","author":"Griendling KK","year":"2000","unstructured":"KK Griendling, D Sorescu, M Ushio-Fukai, NAD(P)H oxidase: Role in cardiovascular biology and disease. Circ Res 86, 494\u2013501 (2000).","journal-title":"Circ Res"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1089\/ars.2012.4785","article-title":"Redox control of inflammation in macrophages","volume":"19","author":"Br\u00fcne B","year":"2013","unstructured":"B Br\u00fcne, et al., Redox control of inflammation in macrophages. Antioxid Redox Signal 19, 595\u2013637 (2013).","journal-title":"Antioxid Redox Signal"},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"4061","DOI":"10.1073\/pnas.052712499","article-title":"Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection","volume":"99","author":"Hurt KJ","year":"2002","unstructured":"KJ Hurt, et al., Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection. Proc Natl Acad Sci USA 99, 4061\u20134066 (2002).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","unstructured":"J Lee et al. Angiopoietin-1 guides directional angiogenesis through integrin alphavbeta5 signaling for recovery of ischemic retinopathy. Sci Transl Med 5(203):203ra127. (2013).","DOI":"10.1126\/scitranslmed.3006666"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1403471111","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T07:19:57Z","timestamp":1654586397000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1403471111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,16]]},"references-count":31,"journal-issue":{"issue":"26","published-print":{"date-parts":[[2014,7]]}},"alternative-id":["10.1073\/pnas.1403471111"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1403471111","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.718472137.793501636","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,6,16]]},"assertion":[{"value":"2014-06-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}