Angiotensin II, From Vasoconstrictor to Growth Factor
Authors: Sasa Vukelic, Kathy K. Griendling
Journal: Circulation Research (2014)

A ngiotensin II (Ang II) is today considered as one of the essential factors in the pathophysiology of cardiovascular disease, producing acute hemodynamic and chronic pleiotropic effects.Although now it is widely accepted that these chronic effects are important, Ang II was initially considered only a short-acting, vasoactive hormone.This view was modified a quarter of a century ago when Dr Owens and his group published an article in Circulation Research with initial evidence that Ang II can act as a growth factor that regulates cell hypertrophy.They showed in a series of elegant experiments that Ang II promotes hypertrophy and hyperploidy of cultured rat aortic smooth muscle cells.However, Ang II had no effect on hyperplasia.These findings led to a paradigm shift in our understanding of the roles of growth factors and vasoactive substances in cardiovascular pathology and helped to redirect basic and clinical renin-angiotensin system research during the next 25 years.Ang II is now known to be a pleiotropic hormone that uses multiple signaling pathways to influence most processes that contribute to the development and progression of cardiovascular diseases, ranging from hypertrophy, endothelial dysfunction, cardiac remodeling, fibrosis, and inflammation to oxidative stress.The renin-angiotensin system (RAS) is now considered one of the essential factors in the pathophysiology of cardiovascular disease.The main effector of the RAS, angiotensin II (Ang II), contributes to the development of cardiovascular disease as both an endocrine and a local autocrine/paracrine hormone, producing acute (vasoconstriction, water/salt retention) and more importantly chronic (hypertrophy, hyperplasia, oxidative stress, fibrosis, and inflammation) effects.Today, it is widely accepted that these chronic effects have a critical role in the development and progression of cardiovascular diseases, such as hypertension, atherosclerosis, and heart failure.Initially, Ang II was considered predominantly as a short-acting, vasoactive hormone, and its role in the pathology of cardiovascular disease was thought to result from acute hemodynamic changes.This view was modified a quarter of a century ago when Dr Owens and his group published an article in Circulation Research with initial evidence that Ang II can act as a growth factor that regulates cell hypertrophy. 1This article completely changed our perspective on both the pathophysiology of cardiovascular diseases and the critical contribution of Ang II to them, and this is the focus of the current commentary.Research on Ang II as a central component of the RAS began more than a century ago in 1898 with studies performed by Scandinavian researchers. 2They reported a vasoconstrictor effect of a substance from renal extracts, which they subsequently named renin based on its origin.Interest in the nature of this vasoactive substance released by the kidney was renewed in 1934 when Goldblatt et al 3 demonstrated that clamping dog renal arteries produced chronic hypertension.In the late 1930s, 2 independent groups in Argentina and the United States used the Goldblatt renal ischemia technique to demonstrate secretion of a pressor agent with effects similar to renin. 4,5This short-acting vasoconstrictor was later identified as an octapeptide product of renin and named Ang. 6During the next half-century, a tremendous amount of research was performed describing in detail the interdependence of the RAS components and the mechanism of action of Ang II, the primary effector molecule of this system. 7p to this point, research efforts were mainly focused on the role of Ang II as an acute regulator of vasomotor tone.The first Food and Drug Administration-approved angiotensin-converting enzyme (ACE) inhibitor, captopril, was developed for the treatment of essential hypertension in 1977, 8 based on early experimental data on the effect of Ang II on blood pressure in hypertension and chronic heart failure. 9ACE inhibitors proved to be clinically successful in reducing symptoms of hypertension and heart failure, 10 despite the fact that there was no experimental evidence indicating Angiotensin II, From Vasoconstrictor to Growth Factor A Paradigm Shift