D106-21 Loss of Pericyte Coverage Contributes to Myocardial Capillary Loss in Maladaptive Right Ventricular Failure

Abstract Rationale Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary pressures and progressive right ventricular (RV) failure. While adaptive RV (aRV) remodeling maintains contractile function, maladaptive RV (mRV) remodeling is marked by capillary rarefaction, cardiomyocyte injury, and fibrosis. Cardiac microvascular stability requires coordinated interactions between endothelial cells (ECs) and pericytes (PCs), yet whether impaired EC–PC communication contributes to microvascular loss and RV decompensation remains unknown. Our group has demonstrated that disruption of EC–PC interactions in the pulmonary circulation leads to microvascular rarefaction. Here, we investigated whether a similar mechanism underlies myocardial capillary loss and mRV failure in PAH. Methods RV tissue from healthy donors, aRV, and mRV PAH patients was analyzed. Immunostaining for EC and PC markers followed by confocal microscopy quantified microvascular density and EC–PC coverage. Complementary analysis was performed in rat models of SuHx PAH, monocrotaline (MCT) injury, and pulmonary artery banding (PAB). Primary cardiac ECs and PCs isolated from donor, aRV, and mRV tissues were assessed in Matrigel tube formation assays and caspase-based apoptosis assays. Single-cell RNA sequencing (scRNA-seq) was performed to identify transcriptomic differences across donor and mRV ECs and PCs, with bulk RNA-seq used for validation. Results Human mRV myocardium demonstrated a significant reduction in EC–PC interactions compared to donor and aRV tissue, accompanied by decreased capillary density and increased fibrosis. Across rat SuHx, MCT, and PAB models, mRV similarly showed loss of pericyte coverage and microvascular rarefaction correlating with impaired RV function. In vitro, donor- and aRV-derived PCs supported organized vascular tube networks with robust EC coverage, whereas mRV PCs produced fragmented, unstable networks and displayed significantly higher apoptosis rates.scRNA-seq of mRV PCs revealed upregulation of metabolic reprogramming, proliferation, and inflammatory pathways, with concurrent downregulation of angiogenic, barrier-supporting, oxygen-sensing, and cell–cell communication programs. Bulk RNA-seq confirmed these maladaptive signatures, demonstrating a distinct transcriptional phenotype in mRV PCs. Conclusions Loss of cardiac EC–PC interactions is a defining feature of maladaptive RV remodeling in PAH and is associated with myocardial capillary rarefaction and fibrosis. Functional and transcriptomic analyses indicate that mRV PCs acquire an intrinsically dysfunctional phenotype that limits their ability to support EC stability and microvascular integrity. These findings support a unifying model in which EC–PC disruption contributes to progressive microvascular loss in both the lung and RV in PAH and highlight restoration of EC–PC interactions as a promising therapeutic strategy to prevent RV failure. This abstract is funded by: NIH