{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T18:42:14Z","timestamp":1792694534345,"version":"4.5.0"},"reference-count":76,"publisher":"American Physiological Society","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2016,12,1]]},"abstract":"<jats:p> Coronary microvascular dysfunction (CMD) has been proposed as an important component of diabetes mellitus (DM)- and hypercholesterolemia-associated coronary artery disease (CAD). Previously we observed that 2.5 mo of DM and high-fat diet (HFD) in swine blunted bradykinin (BK)-induced vasodilation and attenuated endothelin (ET)-1-mediated vasoconstriction. Here we studied the progression of CMD after 15 mo in the same animal model of CAD. Ten male swine were fed a HFD in the absence (HFD, n = 5) or presence of streptozotocin-induced DM (DM + HFD, n = 5). Responses of small (\u223c300-\u03bcm-diameter) coronary arteries to BK, ET-1, and the nitric oxide (NO) donor S-nitroso- N-acetylpenicillamine were examined in vitro and compared with those of healthy (Normal) swine ( n = 12). Blood glucose was elevated in DM + HFD (17.6 \u00b1 4.5 mmol\/l) compared with HFD (5.1 \u00b1 0.4 mmol\/l) and Normal (5.8 \u00b1 0.6 mmol\/l) swine, while cholesterol was markedly elevated in DM + HFD (16.8 \u00b1 1.7 mmol\/l) and HFD (18.1 \u00b1 2.6 mmol\/l) compared with Normal (2.1 \u00b1 0.2 mmol\/l) swine (all P &lt; 0.05). Small coronary arteries showed early atherosclerotic plaques in HFD and DM + HFD swine. Surprisingly, DM + HFD and HFD swine maintained BK responsiveness compared with Normal swine due to an increase in NO availability relative to endothelium-derived hyperpolarizing factors. However, ET-1 responsiveness was greater in HFD and DM + HFD than Normal swine (both P &lt; 0.05), resulting mainly from ET<jats:sub>B<\/jats:sub> receptor-mediated vasoconstriction. Moreover, the calculated vascular stiffness coefficient was higher in DM + HFD and HFD than Normal swine (both P &lt; 0.05). In conclusion, 15 mo of DM + HFD, as well as HFD alone, resulted in CMD. Although the overall vasodilation to BK was unperturbed, the relative contributions of NO and endothelium-derived hyperpolarizing factor pathways were altered. Moreover, the vasoconstrictor response to ET-1 was enhanced, involving the ET<jats:sub>B<\/jats:sub> receptors. In conjunction with our previous study, these findings highlight the time dependence of the phenotype of CMD. <\/jats:p>","DOI":"10.1152\/ajpheart.00458.2015","type":"journal-article","created":{"date-parts":[[2016,9,2]],"date-time":"2016-09-02T22:58:39Z","timestamp":1472857119000},"page":"H1339-H1351","source":"Crossref","is-referenced-by-count":66,"title":["Coronary microvascular dysfunction after long-term diabetes and hypercholesterolemia"],"prefix":"10.1152","volume":"311","author":[{"given":"Oana","family":"Sorop","sequence":"first","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands;"},{"name":"Netherlands Heart Institute, Utrecht, The Netherlands; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mieke","family":"van den Heuvel","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands;"},{"name":"Department of Internal Medicine, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nienke S.","family":"van Ditzhuijzen","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent J.","family":"de Beer","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilkka","family":"Heinonen","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard W. 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