Angiotensin II signal transduction in vascular smooth muscle: Pathways activated by specific tyrosine kinases

In this review, the signal events regulated by angiotensin II (AngII) in va scular smooth muscle are analyzed based on activation of specific tyrosine kinases. AngII has been shown to play a critical role in the pathogenesis o f hypertension, inflammation, atherosclerosis, and congestive heart Failure . The expanding role of AngII indicates that multiple signal transduction p athways are likely to be activated in a tissue-specific manner. Although at least three AngII receptors have been characterized, it seems that the Ang II type I receptor (ATIR) is physiologically most important since pharmacol ogic inhibitors of the ATIR block most AngII signal events and have benefic ial effects on cardiovascular disease. The ATIR is a seven transmembrane-sp anning G protein-coupled receptor that regulates intracellular signal event s by activation of G(q) and G(i). However, many recent data indicate that a ctivation of tyrosine kinases by several different mechanisms contributes t o AngII effects in target tissues. Tyrosine kinases activated by AngII incl ude c-Src, focal adhesion kinase (FAK), Pyk2 (CADTK), Janus kinases (JAK2 a nd TYK2), and the receptor tyrosine kinases Ax1, epidermal growth Factor, a nd platelet-derived growth factor. Finally, unknown tyrosine kinases may me diate tyrosine phosphorylation of paxillin, Shc, Raf, and phospholipase C-g amma after AngII stimulation. These AngII-regulated tyrosine kinases seem t o be required for AngII effects such as vasoconstriction, proto-oncogene ex pression, and protein synthesis based on studies with tyrosine kinase inhib itors. Thus, understanding AngII-stimulated signaling events, especially th ose related to tyrosine kinase activity, may form the basis for the develop ment of new therapies for cardiovascular diseases.