Mechanism of Angiotensin II-mediated Regulation of Fibronectin Gene in Rat Vascular Smooth Muscle Cells

Abstract

Hemodynamic and endocrine factors are among the most important factors implicated in the physiology and pathophysiology of the vascular wall. Arterial hypertension evokes structural and functional changes of the vascular wall (1, 2). Modifications of the extracellular matrix, including fibronectin (FN) 1 and collagen, have been previously reported in vessel walls of hypertensive animals (3-5). Activation and qualitative changes in the extracellular matrix participate in vascular wall remodeling and in the pathogenesis of atherosclerosis. Vascular remodeling in hypertension may be an adaptive response to increased transmural pressure (6 -9). Mechanical stress seems to play a direct role in vascular remodeling, since mechanical stretch is able to increase protein synthesis by vascular smooth muscle cells (VSMCs) (10). However, neuronal and humoral factors may be critical in hypertension-induced remodeling of vascular wall. Especially, several in vivo studies have reported that hypertension activates the vascular renin-angiotensin system (RAS) including angiotensin-converting enzyme (ACE) (11), and infusion of pressor and subpressor doses of angiotensin II (Ang II) increases aortic FN mRNA in both hypertensive and normotensive animals (12, 13). Ang II evokes diverse physiological response including arterial vasoconstriction to elevate blood pressure in vivo (14) and increases production of collagen with a growth-promoting effect on VSMCs in vitro (15). Pharmacological evidence has defined at least two subtypes of Ang II receptors, Ang II type 1 (AT1) receptor and Ang II type 2 (AT2) receptor. Previous results of molecular cloning have revealed that both receptor subtypes belong to the superfamily of G protein-coupled receptors with seven transmembrane helices (16 -19). According to the recent results of in vitro studies, Ang II initially activates a phosphatidylinositol-specific phospholipase C (PI-PLC) via its binding to AT1 receptor on the surface of VSMCs, leading to the generation of inositol triphosphate and diacylglycerol (20), which are involved in intracellular Ca 2ϩ mobilization (21) and protein kinase C (PKC) activation (22), respectively. In VSMCs, Ang II also induces a rapid increase in expression of the growth-associated nuclear protooncogenes and stimulates tyrosine phosphorylation of multiple substrates (23, 24). These findings, taken together with relatively abundant expression of AT1 receptor in vascular wall and VSMCs, indicate that Ang II plays an important role in vascular remodeling via an AT1 receptor pathway. Thus, investigation of the mechanism of Ang II-induced regulation of extracellular matrix and tissue RAS in VSMCs is essential in elucidating the mechanism of vascular remodeling and the pathogenesis of atherosclerosis.In the present study, we examined the effects of Ang II on gene expression of extracellular matrix components (FN and

Extracellular signal-regulated kinase (ERK) in glucose-induced and endothelin-mediated fibronectin synthesis

“…[28][29][30] FN gene has both NF-kB and AP-1 binding site on its promoter and may be positively regulated by both transcription factors. [31][32][33][34][35] Data from our present study would suggest that MAPK pathway may upregulate FN via NF-kB and AP-1. However, it is possible that glucose-induced PKC and ET-1 activation may also lead to FN upregulation independent of MAPK activation.…”

Lipoxygenase Products Regulate Nitric Oxide and Inducible Nitric Oxide Synthase Production in Interleukin-1.BETA. Stimulated Vascular Smooth Muscle Cells.

“…VSMCs from the thoracic aorta of 4-week-old male Wistar rats were prepared by the explant method and cultured in D-MEM medium containing 10% FBS at 37 ºC in a humidified atmosphere of 95% air and 5% CO2 as described previously (20). The cells were studied up to the ninth passage.…”

Distinct Effects of N-Acetylcysteine and Nitric Oxide on Angiotensin II-induced Epidermal Growth Factor Receptor Phosphorylation and Intracellular Ca2+ Levels

“…Most studies have focused on either the vascular smooth muscle cell or the cardiac fibroblast to dilineate the intracellular steps involved in the activation of the MAP kinase system, a characteristic response now associated with hypertrophy, proliferation, or apoptosis (1)(2)(3). This kinase cascade has been shown to be under complex regulation, and its activation by Ang II has been used as a model for the study of how G protein-linked receptors can influence systems normally activated by tyrosine kinase-linked receptors (4 -6).…”