Angiotensin II Regulates Vascular and Endothelial Dysfunction: Recent Topics of Angiotensin II Type-1 Receptor Signaling in the Vasculature

Abstract

Accumulating evidence strongly implicates angiotensin II (AngII) intracellular signaling in mediating cardiovascular diseases such as hypertension, atherosclerosis and restenosis after vascular injury. In vascular smooth muscle cells (VSMCs), through its G-protein-coupled AngII Type 1 receptor (AT(1)), AngII activates various intracellular protein kinases, such as receptor or non-receptor tyrosine kinases, which includes epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Src, PYK2, FAK, JAK2. In addition, AngII activates serine/threonine kinases such as mitogen-activated protein kinase (MAPK) family, p70 S6 kinase, Akt/protein kinase B and various protein kinase C isoforms. In VSMCs, AngII also induces the generation of intracellular reactive oxygen species (ROS), which play critical roles in activation and modulation of above signal transduction. Less is known about endothelial cell (EC) AngII signaling than VSMCs, however, recent studies suggest that endothelial AngII signaling negatively regulates the nitric oxide (NO) signaling pathway and thereby induces endothelial dysfunction. Moreover, in both VSMCs and ECs, AngII signaling cross-talk with insulin signaling might be involved in insulin resistance, an important risk factor in the development of cardiovascular diseases. In fact, clinical and pharmacological studies showed that AngII infusion induces insulin resistance and AngII converting enzyme inhibitors and AT(1) receptor blockers improve insulin sensitivity. In this review, we focus on the recent findings that suggest the existence of novel signaling mechanisms whereby AngII mediates processes, such as activation of receptor or non-receptor tyrosine kinases and ROS, as well as cross-talk between insulin and NO signal transduction in VSMCs and ECs.

Angiotensin-(1-7) Through Receptor Mas Mediates Endothelial Nitric Oxide Synthase Activation via Akt-Dependent Pathways

“…6 Many risk factors implicated in cardiovascular diseases seem to be associated with impairment in the NO system with a reduction in endothelial generation of NO by endothelial NO synthase (eNOS). 5,6 eNOS activity is regulated by various kinases, which induce coordinated phosphorylation of specific sites. 7 Phosphorylation of eNOS at Ser1177 by the phosphatidylinositol 3Ј-kinase (PI3K)/protein kinase B/Akt pathway results in a 2-fold increase in eNOS catalytic activity and NO production.…”

“…2 Overactivity of the renin-angiotensin system, as observed in cardiovascular diseases, and the lack of balance among its peptides may reduce NO bioavailability leading to endothelial dysfunction. 4,5 NO plays a critical role in endothelial function, maintaining vasodilator tone, inhibiting platelet aggregation and adhesion, and modulating vascular smooth muscle cell contraction and proliferation. 6 Many risk factors implicated in cardiovascular diseases seem to be associated with impairment in the NO system with a reduction in endothelial generation of NO by endothelial NO synthase (eNOS).…”

Adiponectin ameliorates angiotensin II-induced vascular endothelial damage

“…Apoptosis of vascular endothelial cells is known to be linked to endothelial dysfunction. Ang II is the main effector of the renin-angiotensin-aldosterone system and has been reported to be involved in various cardiovascular diseases, such as atherosclerosis, hypertension, and heart failure (Nakashima et al 2006). Mechanically, it has been well documented as being implicated in various pro-inflammatory actions in the vascular wall, including adhesion molecule, chemokine, cytokine expression, and ROS generation (Brasier et al 2002).…”

Endothelial dysfunction induced by antibodies against angiotensin AT1 receptor in immunized rats

“…Su-li ZHANG 1, 2 , Yun-hui DU 3 , Jin WANG 1, 2 , Li-hong YANG 1 , Xiao-li YANG 4 , Rong-hua ZHENG 1 , Ye WU 1 , Ke WANG 1 , Mingsheng ZHANG 5 , Hui-rong LIU 3, 1, * More research has proven that, endothelial injury is the common trigger of the series of vascular lesions in both pregnancy-related and pregnancy-unrelated hypertension [13,14] . Now it has been accepted that endothelial injury should be the result of multiple harmful factors, including known and unknown ones.…”

“…At the end of the twentieth century, different research groups had found that there was a high level of autoantibodies against AT1R (AT1-AAs) in preeclampsia [4] , malignant hypertension [5] , refractory hypertension [6] and renal transplantation hypertension [7] . Researchers have paid a lot of attention to this phenomenon.…”