Role of elevated EGFR phosphorylation in the induction of structural remodelling and altered mechanical properties of resistance artery from type 2 diabetic mice.

Background: Type 2 diabetes is associated with microvascular complications. We hypothesized that the sustained elevated EGFR phosphorylation produces structural wall remodelling and altered mechanical properties of mesenteric resistance artery (MRA) in type 2 diabetes.

Methods: Freshly isolated MRA (80-100 microm diameter) from type 2 diabetic (db(-)/db(-), diabetic) and non-diabetic (db(-)/db(+), control) mice were subjected to pressure-passive diameter and wall thickness relationships; western blot analysis and immunohistology.

Role of advanced glycation end products with oxidative stress in resistance artery dysfunction in type 2 diabetic mice.

Objective: Type 2 diabetes is associated with increased advanced glycation end product (AGE) formation and vasculopathy. We hypothesized that AGEs contribute to resistance artery dysfunction.

Methods And Results: Type 2 diabetic db(-)/db(-) (diabetic) and nondiabetic db(-)/db(+) (control) mice were treated with the AGE inhibitor (aminoguanidine: 50 mg/Kg/d) for 3 months.

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.

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).

Elevated epidermal growth factor receptor phosphorylation induces resistance artery dysfunction in diabetic db/db mice.

Objective: We previously showed epidermal growth factor receptor (EGFR) transactivation to be key mechanism in the regulation of resistance artery myogenic tone. Type 2 diabetes is associated with microvascular complications. We hypothesized that elevated EGFR phosphorylation contributes to resistance artery dysfunction in type 2 diabetes.

Role of ACE/AT2R complex in the control of mesenteric resistance artery contraction induced by ACE/AT1R complex activation in response to Ang I.

Objectives: In this study, we will determine the function of the interaction between AT2R and ACE, and AT1R and ACE in the control of mesenteric resistance artery (MRA) tone from normotensive (NT) and Angiotensin II (AII)-dependent hypertensive (HT) mice.

Methods-results: Hypertension was induced by infusion of Ang-II (200 ng/kg/day) for 3 weeks. Freshly MRA (100-120 microm) were isolated from HT and NT mice and mounted in an arteriograph.

Mice lacking the gene encoding for MMP-9 and resistance artery reactivity.

Objectives: To define the link between the deletion of gene encoding for metalloproteinase 9 and resistance artery reactivity, we studied in vitro smooth muscle and endothelial cell function in response to pressure, shear stress, and pharmacological agents.

Background: Matrix metalloproteinases play a crucial role in the regulation of extracellular matrix turnover and structural artery wall remodeling.

Methods: Resistance arteries were isolated from mice lacking gene encoding for MMP-9 (KO) and their control (WT).

Hydrogen peroxide acts as relaxing factor in human vascular smooth muscle cells independent of map-kinase and nitric oxide.

We previously showed that hydrogen peroxide (H2O2) induced resistance artery relaxation independent of endothelium. Thus, in this study we investigated the mechanism of relaxation induced by H2O2 on human renal vascular smooth muscle cell (HVSMC). HVSMC were stimulated with H2O2 and/or angiotensin II (Ang II), proline-rich-tyrosine-kinase-2 (PYK2), ERK1/2 MAP-Kinase, and myosin light chain 20 phosphorylation (Lc20) were assessed using Western blot analysis in the presence of potassium channel blockers, MAP-Kinase, and nitric oxide synthesis (NOS) inhibitors.

Role of SHP-1, Kv.1.2, and cGMP in nitric oxide-induced ERK1/2 MAP kinase dephosphorylation in rat vascular smooth muscle cells.

Objective: Nitric oxide (NO) elicits relaxation in vascular smooth muscle cells (VSMC) that is associated with guanylate cyclase (GC) and K(+) channel activation. In this study we determined the mechanisms that lead to ERK1/2 MAP kinase dephosphorylation in response to NO.

Methods: VSMC were treated with the NO donor SNAP or sodium nitroprusside (SNP), and ERK1/2, Src homology (SH) 1 domain-containing protein tyrosine phosphatase (SHP-1), and Kv.