Angiotensin II Increases Vascular Permeability Factor Gene Expression by Human Vascular Smooth Muscle Cells

Abstract

Angiotensin II (Ang II) has been implicated in the pathogenesis of the vascular injury associated with hypertension and diabetes mellitus. Increased vascular permeability is an important early manifestation of endothelial dysfunction and the pathogenesis of atherosclerosis. How Ang II contributes to endothelial dysfunction and promotes an increase in vascular permeability is unknown but is classically attributed to its pressor actions. We demonstrate that human vascular smooth muscle cells express abundant mRNA for vascular permeability/endothelial growth factor. Vascular permeability factor is a 34- to 42-kD glycoprotein that markedly increases vascular endothelial permeability and is a potent endothelial mitogen. Ang II potently induced a concentration-dependent (maximal, 10(-7) mol/L) and time-dependent increase in vascular permeability factor mRNA expression by human vascular smooth muscle cells that was maximal after 3 hours and diminished by 24 hours. Ang II-induced vascular permeability factor mRNA expression by human vascular smooth muscle cells was inhibited by the specific Ang II receptor antagonist losartan (DuP 753), confirming that this is an Ang II receptor subtype 1-mediated event. These results describe a new action of Ang II on human vascular smooth muscle, notably the induction of vascular permeability factor mRNA expression. The wide spectrum and potent activity of vascular permeability factor suggest a novel mechanism whereby Ang II could locally and directly influence the permeability, growth, and function of the vascular endothelium independent of changes in hemodynamics.

Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes

“…These include not only glucose [37] but also advanced glycation end products (AGEs) [38] and protein kinase-C activation [39,40]. Of particular relevance to our study, angiotensin II also stimulates VEGF expression, an action mediated by the AT1 receptor as indicated by the attenuation of this effect by the AT1 receptor antagonist, losartan [13,41]. Furthermore, in addition to its effects of on VEGF expression, angiotensin II also increases expression of VEGF Receptor-2 (VEGFR-2) [42] thereby potentially increasing tissue responses to VEGF.…”

“…In vitro studies have shown that angiotensin II (AII) directly stimulates the secretion of VEGF in cultured vascular smooth muscle [12] and in cardiac endothelial cells [13]. Whether this relation between the RAS and VEGF secretion applies to the in vivo setting has not, however, been examined.…”

Angiotensin II receptor blocker attenuates overexpression of vascular endothelial growth factor in diabetic podocytes

“…These results describe a new action of angiotensin II on podocytes, notably the induction of VEGF expression. The potent activity of VEGF suggests a novel mech- anism whereby angiotensin II could locally and directly influence the vascular permeability independent of changes in hemodynamics (Williams et al, 1995).…”

Angiotensin converting enzyme inhibiting therapy is associated with lower vitreous vascular endothelial growth factor concentrations in patients with proliferative diabetic retinopathy

“…ACE inhibitors attenuate the formation of angiotensin II and the break-down of bradykinin. Studies in vitro have shown that angiotensin II is able to stimulate the expression of VEGF in bovine retinal pericytes [20], rat heart endothelial cells [26], as well as human vascular smooth muscle [10,16,17] and mesangial cells [18,19]. Moreover, increased concentrations of angiotensin II have been found in the vitreous fluid of patients with proliferative diabetic retinopathy [13,14].…”

“…Diabetic children with increased plasma concentrations of prorenin are at a high risk for the development of retinopathy [15]. In vitro studies indicate that angiotensin II stimulates the secretion of VEGF by vascular smooth muscle cells [10,16,17], mesangial cells [18,19] and pericytes [20]. The induction of VEGF by angiotensin II requires hyperglycaemic [16] or oxidative conditions [17], which are states that accompany diabetes.…”