Idiopathic pulmonary arterial hypertension (IPAH) is a lethal disorder characterized by pulmonary vasoconstriction and remodeling, leading to progressively worsening right ventricular hypertrophy, and eventually right heart failure. The familial form of IPAH is usually due to mutations in the type 2 receptor for the bone morphogenic protein pathway, BMPR2. BMPR2 can signal through several different pathways, including SMAD 1/5/8 and both p38 and p42/44 MAPK. The BMPR2 mutations in human IPAH patients frequently appear to leave SMAD signaling intact, whereas mutations leading to constitutive activation of both p38 and p42/44 MAPK are common. This strongly suggests that, in vivo in human patients, it is loss of BMPR2-mediated suppression of MAPK, rather than loss of SMAD signaling, that leads to the pulmonary hypertensive phenotype. We therefore hypothesize that it is dysregulation of p38 and p42/44 MAPK signaling through BMPR2 which leads to defects both in vasoreactivity and in pulmonary vascular structure, the central hallmarks of PAH. The purpose of this proposal is to directly test this hypothesis in transgenic models of PAH. To do this, we have developed inducible smooth muscle-specific mouse models of PAH which have defects primarily in vasoreactivity (BMPR2-delx4+) or in pulmonary vascular structure (BMPR2-R899X). We intend to (aim 1) determine whether either or both of the phenotypes can be prevented or treated with pharmacologic p38 or p42/44 MAPK inhibitors, (aim 2) determine the molecular pathways that link BMPR2 to elevated p38 and p42/44 MAPK, and (aim 3) determine the molecular consequences of aberrant MAPK signaling through BMPR2, using smooth muscle cells cultured from these animals. Relevance: Evidence from human pulmonary arterial hypertension patients suggests that defective MAPK signaling through BMPR2 causes disease. This study will determine how and whether defective MAPK signaling results in these problems, and will attempt interventions to effect prevention or treatment. We will do this using new mouse models which replicate both the mutations and the central characteristics of human disease, as well as cells cultured from these animals, with the goal of developing more effective therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Moore, Timothy M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Talati, Megha; West, James; Zaynagetdinov, Rinat et al. (2014) BMP pathway regulation of and by macrophages. PLoS One 9:e94119
West, James D; Austin, Eric D; Gaskill, Christa et al. (2014) Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension. Am J Physiol Cell Physiol 307:C415-30
Hemnes, Anna R; Brittain, Evan L; Trammell, Aaron W et al. (2014) Evidence for right ventricular lipotoxicity in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med 189:325-34
Chen, Wen-Chi; Park, Sung-Hyun; Hoffman, Carol et al. (2013) Right ventricular systolic pressure measurements in combination with harvest of lung and immune tissue samples in mice. J Vis Exp :e50023
West, James; Niswender, Kevin D; Johnson, Jennifer A et al. (2013) A potential role for insulin resistance in experimental pulmonary hypertension. Eur Respir J 41:861-71
Park, Sung-Hyun; Chen, Wen-Chi; Hoffman, Carol et al. (2013) Modification of hemodynamic and immune responses to exposure with a weak antigen by the expression of a hypomorphic BMPR2 gene. PLoS One 8:e55180
Johnson, Jennifer A; Hemnes, Anna R; Perrien, Daniel S et al. (2012) Cytoskeletal defects in Bmpr2-associated pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 302:L474-84
Lane, Kirk L; Talati, Megha; Austin, Eric et al. (2011) Oxidative injury is a common consequence of BMPR2 mutations. Pulm Circ 1:72-83
Menon, S; Fessel, J; West, J (2011) Microarray studies in pulmonary arterial hypertension. Int J Clin Pract Suppl :19-28
Nagayoshi, Masaru; Tada, Yuji; West, James et al. (2011) Inhalation of Stachybotrys chartarum evokes pulmonary arterial remodeling in mice, attenuated by Rho-kinase inhibitor. Mycopathologia 172:5-15

Showing the most recent 10 out of 19 publications