| First Author | Young KA | Year | 2006 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 290 |
| Issue | 5 | Pages | L841-8 |
| PubMed ID | 16339782 | Mgi Jnum | J:115767 |
| Mgi Id | MGI:3692167 | Doi | 10.1152/ajplung.00158.2005 |
| Citation | Young KA, et al. (2006) BMP signaling controls PASMC KV channel expression in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 290(5):L841-8 |
| abstractText | 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(V)1.1, K(V)1.5, and K(V)4.3 mRNA isolated from whole lung. Western blot confirmed decreased K(V)1.5 protein in these lungs. Human pulmonary artery smooth muscle cells (PASMC) treated with recombinant BMP2 had increased K(V)1.5 protein and macroscopic K(V) current density, which was blocked by anti-K(V)1.5 antibody. In vivo, nifedipine, a selective L-type Ca(2+) 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 Ca(2+) channels caused by reduced K(V)1.5 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. |
