Proliferation and migration of VSMCs (Vascular Smooth Muscle Cells) in arteries plays an important role in the pathophysiology of atherosclerosis, hypertension, and restenosis after angioplasty. A wide variety of growth factors, cytokines, and hormones activate these responses in blood vessels. A prominent growth factor for VSMCs is Angiotensin (Angiotensin-I and II), the main peptide of the Renin Angiotensin System. Renin, an enzyme acts upon a circulating substrate, angiotensinogen that undergoes proteolytic cleavage to form the decapeptide Angiotensin-I. Vascular endothelium, particularly in the lungs, has an enzyme, ACE (Angiotensin Converting Enzyme), that cleaves off two amino acids to form the octapeptide, Angiotensin-II. Multiple signal transduction pathways are involved in mediating Angiotensin receptor stimulation of cell proliferation, cell migration, and other responses. In addition, activation of Angiotensin receptors has been found to increase prostanoid synthesis in smooth muscle cells, which contributes to some cellular responses mediated by Angiotensin-II (Ref.1). While these three proteins are distinct in their sequence and physiology, and act through different cell surface receptors, they share a common class of cell surface receptors called GPCRs (G-Protein Coupled Receptors).
Angiotensin-II is a potent renal growth factor, inducing hyperplasia/hypertrophy depending on the cell type. This vasoactive peptide activates mesangial and tubular cells and interstitial fibroblasts, increasing the expression and synthesis of ECM
(Extracellular Matrix) proteins. Some of these effects are mediated by the release of several factors, including TGF-Beta (Transforming Growth Factor-Beta) and PAI1 (Plasminogen Activator Inhibitor Type-1) (Ref.2). Angiotensin-II receptors, AgtR1 and AgtR2 subtypes act through G-AlphaQ and GN-AlphaI proteins, respectively. Angiotensin-II, via AgtR1, activates various nuclear transcription factors, including STAT (Signal Transducer and Activator of Transcription) family of transcription factors, and CREB (cAMP Response Element-Binding Protein) (Ref.3). Angiotensin-II increases Ca2+ release and activates PKC (Protein Kinase-C), PTK (Protein Tyrosine Kinases: PYK2, Src and FAK [Focal Adhesion Kinase]), MAPK (Mitogen-Activated Protein Kinase), ERK (Extracellular Signal Regulated Kinase), JNK (c-Jun N-terminal Kinase), p38MAPK , IKK (I-KappaB Kinases) and their downstream effectors such as Elk1, Activating Protein-1, etc. Rac1 activates PYK2 and a small G-protein-activated kinase PAK1 (p21-Activated Kinase). The JNK cascade, including MEKK1/2 (MAP Kinase Kinase), SEK1, and JNK, causes induction of c-Jun gene via binding of ATF2 (Activating Transcription Factor-2).
Angiotensin-II binding to the AgtR1 also stimulates the phosphoinositide-specific PLC (Phospho Lipase-C) to hydrolyze PIP2 (Phosphatidylinositol-4,5-Bisphosphate), thereby generating the second messengers IP3 (Inositol Triphosphate), and DAG (Diacylglycerol) (Ref.3). The intracellular mechanisms elicited by AgtR2 are ceramide production, activation of PPtase (Protein-Phosphotyrosine Phosphatase) and inhibition of MAPK. Ceramide production is involved in apoptosis and NF-KappaB (Nuclear Factor-KappaB) activation. Other important candidates of the AgtR2-NF-KappaB pathway are inducible NO (Nitric Oxide) synthase and COX2 (Cyclooxygenase-2), which in inflammatory diseases are involved in NO/cGMP, Ptg (Prostaglandin) and thromboxane production, respectively. Angiotensin-II may cause growth via AgtR1 and apoptosis via AgtR2. (Ref.2). Activation of the Renin Angiotensin System in tissue also enhances the vascular production of ROS (Reactive Oxygen Species), in part through the activation of membrane-bound NADH (Nicotinamide Adenine Dinucleotide) and NADPH oxidases. These oxidase enzymes are present in endothelial cells, VSMC, fibroblasts, and phagocytic mononuclear cells (Ref.4). Angiotensin-II binding stimulates tyrosine phosphorylation of the linker protein SHC (SH2 Containing Protein), which then interacts with the GRB2-SOS complex, causing activation of Ras. Ras/Raf then stimulates ERK1/2, which phosphorylates the transcription factor p62TCF (Ternary Complex Factor). p62TCF translocates to the nucleus, where it forms a complex at the SRE (Serum Response Element) of the c-Fos gene. The c-Fos promoter also contains a SIE (sis-Inducing Factor Element), which interacts with members of the STAT family of transcription factors. In VSMCs, Angiotensin-II increases production of Ptg, thereby activating AC (Adenyl Cyclase), increasing cAMP, and stimulating PKA (Protein Kinase-A) (Ref.3).
Angiotensin-II, is the dominant effector of the Renin Angiotensin System, which regulates numerous physiological responses, including salt and water balance, blood pressure, and vascular tone. Angiotensin-II plays an important role in various cardiovascular diseases associated with VSMC growth and vessel wall inflammation, such as hypertension, atherosclerosis, and restenosis following interventional procedures (Ref.3). Angiotensin-II increases blood pressure by increasing ADH (Antidiuretic Hormone) secretion from the hypothalamus. It is a very potent vasoconstrictor. It causes the blood vessels to constrict their diameter; thereby increasing the resistance to blood flow and this increases Total Peripheral Resistance. Angiotensin-II acts on the cardiovascular control centre to increase the cardiac output in the heart, which increases blood pressure, and on the adrenal cortex of the adrenal glands to produce more aldosterone, a steroid hormone that promotes the retention of sodium in the kidney. Water is also reabsorbed with the sodium, and this increases blood volume. Angiotensin-II is involved in the inflammatory process during renal injury. It activates inflammatory cells, by direct chemotaxis and production of proinflammatory mediators, including leukocyte adhesion molecules such as VCAM (Vascular Cell Adhesion Molecule), MCP1 (Monocyte Chemoattractant Protein-1), IL-6 (Interleukin-6), and TGF-Beta. It contributes to the ongoing inflammation, facilitating the migration of mononuclear cells to the interstitium and glomeruli where they maturate to macrophages and, ultimately participate in fibrogenesis. These inflammatory cells in turn, activate renal cells through the release of growth factors, including Angiotensin-II, and therefore contribute to the perpetuation of kidney damage. Angiotensin-II regulates mesangial cell growth, inducing proliferation or hypertrophy depending on the intracellular balance between growth factors, and increases the expression and synthesis of ECM proteins, such as fibronectin, laminin, and collagens (Ref.2). In addition to the Renin Angiotensin System in the circulating blood, there are also independent Renin Angiotensin System localized in such areas as the heart, vascular walls, kidneys, and central nervous system. These localized systems play important roles in the progression of the pathological changes associated with hypertension such as heart failure, myocardial infarction, renal failure, and atherosclerosis. Therapeutic manipulation of this pathway has become very important in treating hypertension and heart failure. It is used to decrease arterial pressure, ventricular afterload, blood volume and hence ventricular preload, as well as inhibit and reverse cardiac and vascular hypertrophy. Treatment with blockers of Angiotensin-II actions, such as ACE inhibitors or AgtR1 antagonists, retards disease progression in humans and ameliorates proteinuria, inflammatory cell infiltration, and fibrosis in kidney damage. Ample evidence supports the recommendation of ACE inhibition therapy as the standard cure for strategies aimed to preserve renal function in Chronic Renal Failurehaa. In addition, a better understanding of the nonhemodynamic actions of the Renin Angiotensin System may lead to improved therapies for renal fibrosis and in the treatment of depression, anxiety and cognitive disorders including Alzheimers Disease (Ref.2).