Angiotensin II Signaling in Vascular Physiology and Pathophysiology

Initially recognized as a physiologic regulator of blood pressure and body fluid homeostasis, angiotensin (Ang) II has now been shown in innumerable experiments and clinical studies to contribute to the development and maintenance of cardiovascular disease. Dissection of its signaling mechanisms over the past decades has led to the discovery of several novel concepts, such as tissue-specific metabolism of Ang peptides. Identification and cloning of the various receptors through which Ang II acts on almost all tissues has led to the development of specific pharmacologic inhibitors with proven clinical benefit in patients with cardiovascular disorders. Work on the G-protein-coupled Ang II Type 1 receptor has demonstrated that different receptors interact through oligomerization, compartmentalization, and transactivation, and may explain how Ang II can activate G-protein-independent pathways. Unraveling the downstream effects of Ang II in specific cell types corroborates the importance of the cellular redox state on certain signaling pathways. Finally, the effects of Ang II on cell function and phenotype, such as the expression of inflammatory cytokines and receptors promoting the recruitment of inflammatory cells into vascular tissues, have indicated its role in local inflammation as a general pathogenetic basis of cardiovascular disease. The recognition of Ang II as a contributor to such fundamental pathophysiologic mechanisms, which are believed to be a common pathway for diverse cardiovascular risk factors like hypertension and diabetes, has greatly advanced our knowledge of pathologic signaling in vascular tissues and may help to eventually define novel targets for pharmacologic interventions.