Emerging Roles for Connexins in Hypertension

The current pharmacological arsenal for treating hypertension includes diuretics, inhibition of the Renin- Angiotensin-Aldosterone (RAA) cascade and alpha blockade, often with inadequate results. Gap junction proteins, connexins (Cx), are ubiquitously expressed in organs involved in the pathogenesis of hypertension, namely brain, heart, vascular bed and kidney. Central to hypertension is increased vasomotor tone, itself determined by both paracrine mediators as well as by cell-cell interaction mediated by connexins. Four connexins are involved (Cx37, Cx40, Cx43 and Cx45); their expression patterns and function differ both in physiological conditions as well as in disease states such as hypertension and atherosclerosis. Cx37, Cx40 and Cx43 are expressed in endothelial cells, whereas Cx43 and Cx45 are mostly expressed in vascular smooth muscle cells. Animal models demonstrate a distinct role of Cx40 and Cx43 in renal hypertension. Furthermore, Cx40-deficient mice are constitutively hypertensive and a polymorphism in the promoter region of the encoding gene is associated with an increased risk of hypertension in humans; both observations imply an independent pathophysiological mechanism for the development of hypertension. Whether modifications of function and expression of connexins are markers or causative for disease remains to be determined. However, modulation of connexin-mediated communication may represent a novel therapeutic approach for hypertension.