title: Bone Morphogenic Protein 4-Smad-Induced Upregulation of Platelet-Derived Growth Factor AA Impairs Endothelial Function.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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 db/db mice compared with nondiabetic controls. Pdgfa-shRNA or Bmp4-shRNA adenovirus reduced serum PDGF-AA concentration in db/db mice. PDGF-AA neutralizing antibody or tail injection with Pdgfa-shRNA adenovirus improved endothelial function in aortas and mesenteric resistance arteries from db/db mice. The effect of PDGF-AA on endothelial function in mouse aorta was also inhibited by Ad-Pdgfra-shRNA to inhibit PDGFRα.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Weining
authors.initials: W
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Lau
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Jiang-Yun
authors.initials: JY
authors.lastname: Luo
authors.affiliation: 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.
authors.forename: Lingshan
authors.initials: L
authors.lastname: Gou
authors.affiliation: 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.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Yao
authors.affiliation: 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.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Ronald Ching Wan
authors.initials: RC
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Tian
authors.affiliation: 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. yu-huang@cuhk.edu.hk.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016022:Case-Control Studies; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D034622:RNA Interference; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051896:Smad Proteins, Receptor-Regulated / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D046509:Tissue Culture Techniques; D014162:Transfection; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D057134:Antibodies, Neutralizing; C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D010982:Platelet-Derived Growth Factor; D051896:Smad Proteins, Receptor-Regulated; D014665:Vasodilator Agents; C075278:platelet-derived growth factor A; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: diabetes mellitus; endothelial dysfunction; platelet-derived growth factor; vascular reactivity