title: Microvessel vascular smooth muscle cells contribute to collagen type I deposition through ERK1/2 MAP kinase, alphavbeta3-integrin, and TGF-beta1 in response to ANG II and high glucose.
abstract: This study determines that vascular smooth muscle cell (VSMC) signaling through extracellular signal-regulated kinase (ERK) 1/2-mitogen-activated protein (MAP) kinase, alphavbeta(3)-integrin, and transforming growth factor (TGF)-beta1 dictates collagen type I network induction in mesenteric resistance arteries (MRA) from type 1 diabetic (streptozotocin) or hypertensive (HT; ANG II) mice. Isolated MRA were subjected to a pressure-passive-diameter relationship. To delineate cell types and mechanisms, cultured VSMC were prepared from MRA and stimulated with ANG II (100 nM) and high glucose (HG, 22 mM). Pressure-passive-diameter relationship reduction was associated with increased collagen type I deposition in MRA from HT and diabetic mice compared with control. Treatment of HT and diabetic mice with neutralizing TGF-beta1 antibody reduced MRA stiffness and collagen type I deposition. Cultured VSMC stimulated with HG or ANG II for 5 min increased ERK1/2-MAP kinase phosphorylation, whereas a 48-h stimulation induced latent TGF-beta1, alphavbeta(3)-integrin, and collagen type 1 release in the conditioned media. TGF-beta1 bioactivity and Smad2 phosphorylation were alphavbeta(3)-integrin-dependent, since beta(3)-integrin antibody and alphavbeta(3)-integrin inhibitor (SB-223245, 10 microM) significantly prevented TGF-beta1 bioactivity and Smad2 phosphorylation. Pretreatment of VSMC with ERK1/2-MAP kinase inhibitor (U-0126, 1 microM) reduced alphavbeta(3)-integrin, TGF-beta1, and collagen type 1 content. Additionally, alphavbeta(3)-integrin antibody, SB-223245, TGF-beta1-small-intefering RNA (siRNA), and Smad2-siRNA (40 nM) prevented collagen type I network formation in response to ANG II and HG. Together, these data provide evidence that resistance artery fibrosis in type 1 diabetes and hypertension is a consequence of abnormal collagen type I release by VSMC and involves ERK1/2, alphavbeta(3)-integrin, and TGF-beta1 signaling. This pathway could be a potential target for overcoming small artery complications in diabetes and hypertension.
authors.affiliation: Dept. of Physiology, Hypertension & Renal Center of Excellence, Tulane Univ., School of Medicine, Health Sciences Center, New Orleans, Louisana, USA.
authors.forename: Souad
authors.initials: S
authors.lastname: Belmadani
authors.forename: Mourad
authors.initials: M
authors.lastname: Zerfaoui
authors.forename: Hamid A
authors.initials: HA
authors.lastname: Boulares
authors.forename: Desiree I
authors.initials: DI
authors.lastname: Palen
authors.forename: Khalid
authors.initials: K
authors.lastname: Matrougui
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000804:Angiotensin II; D000818:Animals; D000906:Antibodies; D001570:Benzodiazepinones / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D004548:Elasticity; D005355:Fibrosis; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D008638:Mesenteric Arteries / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000085:Acetates; D000906:Antibodies; D001570:Benzodiazepinones; D001786:Blood Glucose; D024042:Collagen Type I; D039302:Integrin alphaVbeta3; C121648:SB 223245; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3