BMP signaling controls PASMC KV channel expression in vitro and in vivo

Abstract

Bone morphogenetic proteins (BMPs) have been implicated in the pathogenesis of familial pulmonary arterial hypertension. The type 2 receptor (BMPR2) is required for recognition of all BMPs. Transgenic mice with a smooth muscle cell-targeted mutation in this receptor (SM22-tet-BMPR2^delx4+) developed increased pulmonary artery pressure, associated with a modest increase in arterial muscularization, after 8 wk of transgene activation (West J, Fagan K, Steudel W, Fouty B, Lane K, Harral J, Hoedt-Miller M, Tada Y, Ozimek J, Tuder R, and Rodman DM. Circ Res 94: 1109–1114, 2004). In the present study, we show that these transgenic mice developed increased right ventricular pressures after only 1 wk of transgene activation, without significant remodeling of the vasculature. We then tested the hypothesis that the increased pulmonary artery pressure due to loss of BMPR2 signaling was mediated by reduced K_V channel expression. There was decreased expression of K_V1.1, K_V1.5, and K_V4.3 mRNA isolated from whole lung. Western blot confirmed decreased K_V1.5 protein in these lungs. Human pulmonary artery smooth muscle cells (PASMC) treated with recombinant BMP2 had increased K_V1.5 protein and macroscopic K_V current density, which was blocked by anti-K_V1.5 antibody. In vivo, nifedipine, a selective L-type Ca²⁺ channel blocker, reduced RV systolic pressure in these dominant-negative BMPR2 mice to levels seen in control animals. This suggests that activation of L-type Ca²⁺ channels caused by reduced K_V1.5 mediates increased pulmonary artery pressure in these animals. These studies suggest that BMP regulates K_V channel expression and that loss of this signaling pathway in PASMC through a mutation in BMPR2 is sufficient to cause pulmonary artery vasoconstriction.