Connexin37-Dependent Mechanisms Selectively Contribute to Modulate Angiotensin II-Mediated Hypertension

Abstract

Background: Gap junction channels made of Connexin37 (Cx37) are expressed by aortic endothelial and smooth muscle cells of hypertensive mice, as well as by the renin-secreting cells of kidneys. Methods and Results: To decipher whether Cx37 has any role in hypertension, angiotensin II (Ang II) was infused in normotensive wild-type and Cx37-deficient mice (Cx37−/−). After 2 to 4 weeks, the resulting increase in blood pressure was lower in Cx37−/− than in wild-type mice, suggesting an alteration in the Ang II response. To investigate this possibility, mice were submitted to a 2-kidney, 1-clip procedure, a renin-dependent model of hypertension. Two weeks after this clipping, Cx37−/− mice were less hypertensive than wild-type mice and, 2 weeks later, their blood pressure had returned to control values, in spite of abnormally high plasma renin levels. In contrast, Cx37−/− and wild-type mice that received N-nitro-l-arginine-methyl-ester, a renin-independent model of hypertension, featured a similar and sustained increase in blood pressure. The data indicate that loss of Cx37 selectively altered the Ang II-dependent pathways. Consistent with this conclusion, aortas of Cx37−/− mice featured an increased basal expression of the Ang II type 2 receptors (AT2R), and increased transcripts levels of downstream signaling proteins, such as Cnksr1 and Ptpn6 (SHP-1). Accordingly, the response of Cx37−/− mice aortas to an ex vivo AngII exposure was altered, since phosphorylation levels of several proteins of the AngII pathway (MLC2, ERK, and AKT) remained unchanged. Conclusions: These findings provide evidence that Cx37 selectively influences Ang II signaling, mostly via a modulation of the expression of the Ang II type 2 receptor.