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

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.