The Renin Angiotensin System in the Regulation of Angiogenesis

S.   C.   Heffelfinger

Abstract

Decades of experimentation on angiotensin and bradykinin have focused on macrovascular systemic effects. However, angiotensin II and bradykinin are both angiogenic agents, highlighting their ability to also effect the microvascular circulation. Not surprisingly, inhibition of angiotensin converting enzyme, which inhibits angiotensin II synthesis and bradykinin degradation, would have different impacts on angiogenesis in vivo dependent upon what factors were present in the system. Several pathological states in which angiogenesis is important, including peripheral ischemia, stroke, retinopathy, and cancer are examined in this review with respect to activity of angiotensin II and bradykinin and the impact of angiotensin converting enzyme inhibition. Although generalizations are not without legitimate criticism, one can think about peripheral ischemia and stroke as being more dependent upon bradykinin signaling and retinopathy and cancer as more dependent upon angiotensin II signaling to drive angiogenesis. Many exceptions are found that are specific to individual animal model systems. Furthermore, cancer systems that have been examined at any depth are few. However, published data on in vitro cultures and animal models present interesting predictions about how the renin angiotensin and bradykinin systems may function in humans. Since angiotensin converting enzyme inhibitors have been widely utilized pharmaceuticals for many years, we are now accumulating epidemiological data that test our predictions. The importance of understanding which agent, angiotensin and/or bradykinin, appears to be the more important regulator of angiogenesis in a given pathology will become increasing evident as more specific angiotensin II and bradykinin receptor blocking drugs make their way into clinical use.

Keywords: Angiotensin, bradykinin, ischemia, cancer, angiogenesis, stroke, angiotensin converting enzyme, kininogen