Angiotensin II, from vasoconstrictor to growth factor: a paradigm shift

Abstract

Angiotensin 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 a paper in Circulation Research with initial evidence that Ang II can act as a growth factor that regulates cell hypertrophy. They showed in 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 over the next twenty-five years. Ang II is now known to be a pleiotropic hormone that utilizes 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.

Figure 1. Paradigm shift in Angiotensin research: From vasoactive, short acting hormone to pleiotropic growth factor and immunomodulator

Dr. Owens findings that Ang II is not just an acute vasoactive substance, but also a potent growth factor inspired multiple new studies in different basic research fields from inflammation to tyrosine kinase signaling. These basic research results served as a starting point for clinical research studies that caused a change in therapeutic practices, with ACE inhibitors and ARBs becoming cornerstone of therapy.