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Microvessel vascular smooth muscle cells contribute to collagen type I deposition through ERK1/2 MAP kinase, vβ₃-integrin, and TGF-β1 in response to ANG II and high glucose

Departments of ¹Physiology and ²Pharmacology, Louisiana State Univeristy Health Sciences Center, New Orleans; and ³Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, School of Medicine, Health Sciences Center, New Orleans, Louisana

Submitted 1 April 2008 ; accepted in final form 25 April 2008

This study determines that vascular smooth muscle cell (VSMC) signaling through extracellular signal-regulated kinase (ERK) 1/2-mitogen-activated protein (MAP) kinase, vβ₃-integrin, and transforming growth factor (TGF)-β1 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-β1 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-β1, vβ₃-integrin, and collagen type 1 release in the conditioned media. TGF-β1 bioactivity and Smad2 phosphorylation were vβ₃-integrin-dependent, since β₃-integrin antibody and vβ₃-integrin inhibitor (SB-223245, 10 µM) significantly prevented TGF-β1 bioactivity and Smad2 phosphorylation. Pretreatment of VSMC with ERK1/2-MAP kinase inhibitor (U-0126, 1 µM) reduced vβ₃-integrin, TGF-β1, and collagen type 1 content. Additionally, vβ₃-integrin antibody, SB-223245, TGF-β1-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, vβ₃-integrin, and TGF-β1 signaling. This pathway could be a potential target for overcoming small artery complications in diabetes and hypertension.

hypertension; Type 1 diabetes; extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase; transforming growth factor-β1; vascular smooth muscle cell; resistance artery

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