{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:32:31Z","timestamp":1790188351920,"version":"4.1.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>Bone morphogenic protein 4 (BMP4) is an important mediator of endothelial dysfunction in cardio-metabolic diseases, whereas platelet-derived growth factors (PDGFs) are major angiogenic and proinflammatory mediator, although the functional link between these 2 factors is unknown. The present study investigated whether PDGF mediates BMP4-induced endothelial dysfunction in diabetes mellitus.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>\n              We generated Ad-Bmp4 to overexpress Bmp4 and Ad-Pdgfa-shRNA to knockdown Pdgfa in mice through tail intravenous injection. SMAD4-shRNA lentivirus, SMAD1-shRNA, and SMAD5 shRNA adenovirus were used for knockdown in human and mouse endothelial cells. We found that PDGF-AA impaired endothelium-dependent vasodilation in aortas and mesenteric resistance arteries. BMP4 upregulated PDGF-AA in human and mouse endothelial cells, which was abolished by BMP4 antagonist noggin or knockdown of SMAD1\/5 or SMAD4. BMP4-impared relaxation in mouse aorta was also ameliorated by PDGF-AA neutralizing antibody. Tail injection of Ad-Pdgfa-shRNA ameliorates endothelial dysfunction induced by Bmp4 overexpression (Ad-Bmp4) in vivo. Serum PDGF-AA was elevated in both diabetic patients and diabetic\n              <jats:italic>db\/db<\/jats:italic>\n              mice compared with nondiabetic controls. Pdgfa-shRNA or Bmp4-shRNA adenovirus reduced serum PDGF-AA concentration in\n              <jats:italic>db\/db<\/jats:italic>\n              mice. PDGF-AA neutralizing antibody or tail injection with Pdgfa-shRNA adenovirus improved endothelial function in aortas and mesenteric resistance arteries from\n              <jats:italic>db\/db<\/jats:italic>\n              mice. The effect of PDGF-AA on endothelial function in mouse aorta was also inhibited by Ad-Pdgfra-shRNA to inhibit PDGFR\u03b1.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>The present study provides novel evidences to show that PDGF-AA impairs endothelium-dependent vasodilation and PDGF-AA mediates BMP4-induced adverse effect on endothelial cell function through SMAD1\/5- and SMAD4-dependent mechanisms. Inhibition of PGDF-AA ameliorates vascular dysfunction in diabetic mice.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.115.306302","type":"journal-article","created":{"date-parts":[[2016,1,15]],"date-time":"2016-01-15T12:59:31Z","timestamp":1452862771000},"page":"553-560","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Bone Morphogenic Protein 4-Smad\u2013Induced Upregulation of Platelet-Derived Growth Factor AA Impairs Endothelial Function"],"prefix":"10.1161","volume":"36","author":[{"given":"Weining","family":"Hu","sequence":"first","affiliation":[{"name":"From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; and Institute of Diabetes and Obesity (R.C.W.M), Chinese University of Hong Kong, Hong Kong SAR, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; and Institute of Diabetes and Obesity (R.C.W.M), Chinese University of Hong Kong, Hong Kong SAR, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; and Institute of Diabetes and Obesity (R.C.W.M), Chinese University of Hong Kong, Hong Kong SAR, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi Wai","family":"Lau","sequence":"additional","affiliation":[{"name":"From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; and Institute of Diabetes and Obesity (R.C.W.M), Chinese University of Hong Kong, Hong Kong SAR, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Xu","sequence":"additional","affiliation":[{"name":"From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; and Institute of Diabetes and Obesity (R.C.W.M), Chinese University of Hong Kong, Hong Kong SAR, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang-Yun","family":"Luo","sequence":"additional","affiliation":[{"name":"From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; and Institute of Diabetes and Obesity (R.C.W.M), Chinese University of Hong Kong, Hong Kong SAR, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingshan","family":"Gou","sequence":"additional","affiliation":[{"name":"From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; and Institute of Diabetes and Obesity (R.C.W.M), Chinese University of Hong Kong, Hong Kong SAR, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqiang","family":"Yao","sequence":"additional","affiliation":[{"name":"From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; and Institute of Diabetes and Obesity (R.C.W.M), Chinese University of Hong Kong, Hong Kong SAR, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; and Institute of Diabetes and Obesity (R.C.W.M), Chinese University of Hong Kong, Hong Kong SAR, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald Ching Wan","family":"Ma","sequence":"additional","affiliation":[{"name":"From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; and Institute of Diabetes and Obesity (R.C.W.M), Chinese University of Hong Kong, Hong Kong SAR, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao Yu","family":"Tian","sequence":"additional","affiliation":[{"name":"From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; and Institute of Diabetes and Obesity (R.C.W.M), Chinese University of Hong Kong, Hong Kong SAR, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Huang","sequence":"additional","affiliation":[{"name":"From the Shenzhen Research Institute, School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences (W.H., Y.Z., L.W., C.W.L., J.X., J.-Y.L., L.G., X.Y., X.Y.T., Y.H), the School of Life Science (Z.-Y.C.), Department of Medicine and Therapeutics, the Prince of Wales Hospital, Hong Kong; 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