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

• Published in: American journal of physiology. Lung cellular and molecular physiology 2006-05, Vol.290 (5), p.L841-L848
• Main Authors: Young, Katharine A, Ivester, Charles, West, James, Carr, Michelle, Rodman, David M
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Blood Pressure; Bone Morphogenetic Protein Receptors, Type II - deficiency; Bone Morphogenetic Protein Receptors, Type II - genetics; Bone Morphogenetic Protein Receptors, Type II - physiology; Bone Morphogenetic Proteins - physiology; DNA Primers; Humans; Hypertension, Pulmonary - physiopathology; Mice; Mice, Knockout; Mice, Transgenic; Potassium Channels, Voltage-Gated - genetics; Potassium Channels, Voltage-Gated - physiology; Pulmonary Circulation - physiology; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00158.2005

1 University of Colorado at Denver and Health Sciences Center, Center for Genetic Lung Disease, Division of Pulmonary Sciences and Critical Care Medicine; and 2 Cardiovascular Pulmonary Research, Denver, Colorado Submitted 11 April 2005 ; accepted in final form 4 December 2005 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. pulmonary arterial hypertension; voltage-gated potassium channel 1.5; bone morphogenetic protein receptor type 2; vascular tone Address for reprint requests and other correspondence: J. West, Center for Genetic Lung Disease, UCHSC Box B133, 4200 E. 9th Ave., Denver, CO 80262 (e-mail: James.West{at}uchsc.edu )