Molecular drivers of pulmonary vascular remodeling in PH-hfpef

The National Heart, Lung, and Blood Institute awarded the University of Maryland, Baltimore $775,687 under Project Grant R01HL183332 on August 10, 2026, to support research on molecular drivers of pulmonary vascular remodeling in pulmonary hypertension with heart failure and preserved ejection fraction (PH-HFPEF).

The research investigates beta-2 microglobulin (B2M) as a therapeutic target in PH-HFPEF. The project builds on findings that PH-HFPEF patients display elevated circulating B2M levels correlating with disease severity, and that B2M reduction attenuates pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy in metabolic syndrome-associated PH-HFPEF mouse models. The award funds evaluation of an anti-B2M antibody (HB3) developed through phage display screening, testing its ability to neutralize B2M-induced pulmonary artery endothelial cell migration and proliferation, and to reduce circulating B2M in vivo. The research will examine downstream mechanisms involving stabilin-1 (STAB1) expression, cationic amino acid transporter 2 (CAT2) signaling in pulmonary vascular smooth muscle cells, and hypusine-mediated pulmonary vascular remodeling pathways.

Period of performance runs through April 30, 2030, with place of performance in Indianapolis, Indiana. The award is a project grant under the Cardiovascular Diseases Research program (CFDA 93.837), which supports competitive heart, lung, and blood disease research across basic, translational, clinical, and population sciences.

Abstract

Pulmonary hypertension is a common complication with adverse outcomes in patients with heart failure with preserved ejection fraction (PH-hfpef). Although FDA-approved SGLT2 inhibitors have been shown to decrease pulmonary pressures in hfpef patients, the effect was short-term and the mortality rate remains high. We have recently found that PH-hfpef patients display higher circulating levels of Β2- microglobulin (B2M), the magnitude of which correlates with disease severity. Loss of B2M improves glucose intolerance and attenuates pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy in mice with metabolic syndrome-associated PH-hfpef, all of which suggest that B2M-targeting therapies may prove to be highly effective in the treatment of PH-hfpef. This proposal is based on our exciting new data, namely 1) phage display screening identifies highly specific and high-affinity antibody, HB3, against B2M; 2) HB3 administration abolishes B2M-induced pulmonary artery endothelial cells (paecs) migration/proliferation and neutralizes/reduces circulating levels of B2M in vivo; 3) decreased paecs expression of stabilin-1 (STAB1), a scavenger receptor which can also act as an adhesion molecule for immune cell infiltration, is associated with B2M-deficiency-related improvement of PH-hfpef; 4) B2M treatment raises expression of cationic amino acid transporter 2 (CAT2), an arginine transporter involved in nitric oxide (no) and polyamines production, accompanied with increased cell proliferation in pulmonary vascular smooth muscle cells (pvsmcs); and 5) CAT2-overexpressed pvsmcs enhances hypusine signaling, a posttranslational modification which promotes pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Thus, we hypothesize that B2M-targeting therapy with HB3 may be sufficient to improve pulmonary vascular remodeling and PH-hfpef via reducing expression of STAB1 in paecs and CAT2 in pvsmcs. Specific aim 1 will determine the efficacy and mechanistic role of HB3 in PH-hfpef. Using paecs and pvsmcs, EX vivo precision-cut lung slices (pcls), and in vivo PH-hfpef models, we will characterize the impact of HB3 and its interaction with STAB1 and CAT2 in PH-hfpef. In aim 2 and aim 3, we will evaluate whether and how paecs STAB1 and pvsmcs CAT2 contribute to the pulmonary vascular defects in PH- hfpef. Clinical relevance of STAB1 and CAT2 in human disease will also be assessed. We expect that these studies will provide a better picture of still poorly understood pathophysiological processes and molecular mechanisms in PH-hfpef. The outcome of this study may also offer a clearer direction for future therapeutic development/design, especially B2M-targeting therapy, to restore cardiopulmonary health.