Pulmonary hypertension (PH) is associated with pulmonary vascular remodeling that promotes right heart failure and premature death. In PH, pulmonary endothelial dysfunction is identified as a critical mediator of aberrant distal arteriole remodeling to induce pulmonary hypertension. The current WHO classification system segregates PH patients into distinct categories based on predisposing conditions. Despite this, it remains unknown if patients within these groups share a common endothelial or endovascular pathophenotype that is a determinant of disease progression or response to pharmacotherapy. This has led to our hypothesis that an integrated pulmonary artery endothelial (patho)phenotypic analysis will identify previously unrecognized features shared between subsets of patients with PH that will inform on disease status. To address this, we propose 3 specific aims, which are designed to 1) establish an integrated pulmonary artery endothelial profile through microRNA, mRNA, and metabolyte expression analyses using RNA-Seq and proteomics;2) evaluate the pulmonary artery endothelial response to exercise;and 3) correlate the endothelial phenotypic profile with clinical assessments of hemodynamics, right ventricular performance and functional capacity. Studies to profile the pulmonary vascular endothelium will be performed using immediately isolated pulmonary artery endothelial cells obtained at the time of right heart catheterization and plasma samples drawn in the pre- and post- exercise phases of a 6-minute walk test. Using a systems biology approach, data from the advanced phenotypic profiling studies will be incorporated into a network to uncover previously unknown interactions between microRNAs, mRNAs, and metabolic proteins that function as disease modifiers and can be developed further as targets for pharmacotherapies or biomarkers. Integrated endothelial pathophenotypic profiling will be accomplished through collaboration of a multidisciplinary team that includes individuals with expertise in pulmonary vascular disease, cardiology, imaging, cell and molecular biology, and bioinformatics. Completion of the integrated phenotyping proposal will lead to the emergence of key endothelial phenotypes that will redefine our approach to patients with PH.

Public Health Relevance

Pulmonary hypertension is associated with poor clinical outcomes and early death despite currently available medical therapies. Pulmonary hypertension patients are currently categorized according to the disease etiology. This study proposes to characterize the endothelium (inner lining of the pulmonary blood vessels) to identify similarities and differences between patients with the disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-P (S1))
Program Officer
Xiao, Lei
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Elinoff, Jason M; Agarwal, Richa; Barnett, Christopher F et al. (2018) Challenges in Pulmonary Hypertension: Controversies in Treating the Tip of the Iceberg. A Joint National Institutes of Health Clinical Center and Pulmonary Hypertension Association Symposium Report. Am J Respir Crit Care Med 198:166-174
Leopold, Jane A (2018) Pulmonary Venous Remodeling in Pulmonary Hypertension: The Veins Take Center Stage. Circulation 137:1811-1813
Han, Yuchi; Forfia, Paul R; Vaidya, Anjali et al. (2018) Rationale and design of the ranolazine PH-RV study: a multicentred randomised and placebo-controlled study of ranolazine to improve RV function in patients with non-group 2 pulmonary hypertension. Open Heart 5:e000736
Faria-Urbina, Mariana; Oliveira, Rudolf K F; Agarwal, Manyoo et al. (2018) Inhaled Treprostinil in Pulmonary Hypertension Associated with Lung Disease. Lung 196:139-146
Leopold, Jane A; Loscalzo, Joseph (2018) Emerging Role of Precision Medicine in Cardiovascular Disease. Circ Res 122:1302-1315
Samokhin, Andriy O; Stephens, Thomas; Wertheim, Bradley M et al. (2018) NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension. Sci Transl Med 10:
Oldham, William M; Oliveira, Rudolf K F; Wang, Rui-Sheng et al. (2018) Network Analysis to Risk Stratify Patients With Exercise Intolerance. Circ Res 122:864-876
Randles, Amanda; Frakes, David H; Leopold, Jane A (2017) Computational Fluid Dynamics and Additive Manufacturing to Diagnose and Treat Cardiovascular Disease. Trends Biotechnol 35:1049-1061
Newman, John H; Rich, Stuart; Abman, Steven H et al. (2017) Enhancing Insights into Pulmonary Vascular Disease through a Precision Medicine Approach. A Joint NHLBI-Cardiovascular Medical Research and Education Fund Workshop Report. Am J Respir Crit Care Med 195:1661-1670
Leopold, Jane A (2017) Reply: Understanding vascular calcification from an evolutionary approach. Trends Cardiovasc Med 27:70-71

Showing the most recent 10 out of 40 publications