Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of apoptosis-resistant pulmonary artery endothelial cells (PAEC), smooth muscle cells (PASMC), and adventitial fibroblasts (PAAF) leading to progressive increases in pulmonary vascular resistance, and ultimately right heart failure and death. Recent studies suggest that pulmonary arterial (PA) stiffness is associated with increased mortality in patients with PAH; however, the mechanisms involved in the pathogenesis and progression of PA stiffening in PAH have yet to be fully elucidated. We have discovered that distal vascular matrix stiffening develops early in models of pulmonary hypertension (PH) and triggers a local mechanobiological feedback loop that amplifies vascular remodeling and accelerates disease progression. These findings suggest that PA stiffness is not merely a consequence of pathologic changes in the vessel wall, but can itself drive abnormal cellular behavior. We have identified YAP and TAZ as pivotal regulators of stiffness-dependent PASMC and PAEC mechanoactivation in PAH. Our preliminary findings suggest that mechanosignaling via YAP/TAZ drives vascular cell activation through suppression of cyclooxygenase (COX)-2-derived prostanoid production and bone morphogenetic protein (BMP) signaling. Silencing of YAP/TAZ in PASMC and PAEC abrogates stiffness- dependent increases in proliferation, matrix deposition, and traction force generation, and rescues suppression of prostanoid production and BMP signaling. Moreover, PASMC overexpressing a mutant TAZ that localizes constitutively to the nucleus have a dramatic reduction in COX-2-derived prostanoid production and BMP signaling leading to a hyperproliferative remodeling phenotype. We hypothesize that YAP/TAZ are activated by the mechanical environment to drive pro-remodeling cellular responses and promote matrix stiffening in an adverse feedback loop via suppression of prostanoid production and BMP signaling in PAH.
In Aim 1, we will investigate the role that YAP/TAZ play in regulating COX-2-dependent prostaglandin production and vascular responses to matrix stiffening in PAH. We will determine the mechanisms of YAP/TAZ-dependent suppression of COX-2 and regulation of stiffness-dependent contractility and matrix synthesis in human PASMC, PAEC, and PAAF.
In Aim 2, we will examine the mechanisms by which YAP/TAZ control TGF-! and BMP-dependent Smad signaling, suppress Id1 expression, and regulate cellular growth responses to BMP signaling in PAH. We will determine the impact of YAP/TAZ activity on proliferation, apoptosis resistance, and migration in PASMC, PAEC, and PAAF from PAH patients with and without BMPR2 mutations.
In Aim 3, we will determine whether inactivation of YAP/TAZ arrests PA stiffening, attenuates vascular remodeling, and prevents right ventricular (RV) dysfunction in experimental PH. We will use murine models and pharmacologic approaches to modulate YAP/TAZ activity and assess the effects of YAP/TAZ inactivation on PA stiffening, hemodynamics, RV dysfunction, vascular remodeling, and regulation of the prostanoid and BMP pathways in models of PH.

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a severe disease characterized by abnormal growth and behavior of vascular cells within the pulmonary artery wall leading to stiffening and narrowing of pulmonary arteries, which can progress to failure of the right side of the heart and death. The proposed research will investigate a novel pathway through which mechanical and biochemical stimuli converge to activate pulmonary vascular cells and promote PAH. Our studies will examine the molecular mechanisms by which the YAP/TAZ pathway drives matrix stiffening and vascular remodeling in cells from patients with PAH, and determine whether new approaches to therapeutically target this pathway can prevent pulmonary artery stiffening, vascular remodeling, and right heart failure in experimental models of pulmonary hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL137366-01A1
Application #
9456950
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
2018-01-01
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115