Caveolin-1 negatively regulates a metalloprotease-dependent epidermal growth factor receptor transactivation by angiotensin II.

A metalloprotease, ADAM17, mediates the generation of mature ligands for the epidermal growth factor receptor (EGFR). This is the key signaling step by which angiotensin II (AngII) induces EGFR transactivation leading to hypertrophy and migration of vascular smooth muscle cells (VSMCs). However, the regulatory mechanism of ADAM17 activity remains largely unclear.

Endothelial nitric oxide synthase inhibits G12/13 and rho-kinase activated by the angiotensin II type-1 receptor: implication in vascular migration.

Background: Although, endothelial nitric oxide (NO) synthase (eNOS) is believed to antagonize vascular remodeling induced by the angiotensin II (AngII) type-1 receptor, the exact signaling mechanism remains unclear.

Methods And Results: By expressing eNOS to vascular smooth muscle cells (VSMCs) via adenovirus, we investigated a signal transduction mechanism of the eNOS gene transfer in preventing vascular remodeling induced by AngII. We found marked inhibition of AngII-induced Rho/Rho-kinase activation and subsequent VSMC migration by eNOS gene transfer whereas G(q)-dependent transactivation of the epidermal growth factor receptor by AngII remains intact.

Distinct roles of protease-activated receptors in signal transduction regulation of endothelial nitric oxide synthase.

Protease-activated receptors (PARs), such as PAR1 and PAR2, have been implicated in the regulation of endothelial NO production. We hypothesized that PAR1 and PAR2 distinctly regulate the activity of endothelial NO synthase through the selective phosphorylation of a positive regulatory site, Ser(1179), and a negative regulatory site, Thr(497), in bovine aortic endothelial cells. A selective PAR1 ligand, TFLLR, stimulated the phosphorylation of endothelial NO synthase at Thr(497).

Central role of Gq in the hypertrophic signal transduction of angiotensin II in vascular smooth muscle cells.

The angiotensin II (AngII) type 1 receptor (AT(1)) plays a critical role in hypertrophy of vascular smooth muscle cells (VSMCs). Although it is well known that G(q) is the major G protein activated by the AT(1) receptor, the requirement of G(q) for AngII-induced VSMC hypertrophy remains unclear. By using cultured VSMCs, this study examined the requirement of G(q) for the epidermal growth factor receptor (EGFR) pathway, the Rho-kinase (ROCK) pathway, and subsequent hypertrophy.

Novel role of protein kinase C-delta Tyr 311 phosphorylation in vascular smooth muscle cell hypertrophy by angiotensin II.

We have shown previously that activation of protein kinase C-delta (PKC delta) is required for angiotensin II (Ang II)-induced migration of vascular smooth muscle cells (VSMCs). Here, we have hypothesized that PKC delta phosphorylation at Tyr(311) plays a critical role in VSMC hypertrophy induced by Ang II. Immunoblotting was used to monitor PKC delta phosphorylation at Tyr(311), and cell size and protein measurements were used to detect hypertrophy in VSMCs.

Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology.

The intracellular signal transduction of AngII (angiotensin II) has been implicated in cardiovascular diseases, such as hypertension, atherosclerosis and restenosis after injury. AT(1) receptor (AngII type-1 receptor), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of AngII, and this receptor is predominantly expressed in cardiovascular cells, such as VSMCs (vascular smooth muscle cells). AngII activates various signalling molecules, including G-protein-derived second messengers, protein kinases and small G-proteins (Ras, Rho, Rac etc), through the AT(1) receptor leading to vascular remodelling.

Small GTP-binding proteins and mitogen-activated protein kinases as promising therapeutic targets of vascular remodeling.

Purpose Of Review: To summarize the most recent findings concerning the targeting of mitogen-activated protein kinases and small GTP-binding proteins toward vascular remodeling together with molecular mechanisms of their activations in vascular pathophysiology.

Recent Findings: In addition to targeting the classical Ras/extracellular signal-regulated kinase cascade, Rho-kinase inhibitors, as well as the HMG-CoA reductase inhibitors, or 'statins', have pleiotropic efficacy for experimental cardiovascular diseases that involve inhibition of the signal transduction cascades originated by the small GTP-binding proteins such as Rho and Rac. Moreover, the underlying molecular mechanisms of the activation of these small GTP-binding proteins and downstream mitogen-activated protein kinases in cardiovascular tissue and cells have recently been better characterized.