Abstract 15699: A Wolf in Sheep’s Clothing- CD13 Activation Mediates Pericyte to Smooth Muscle Cell Switch in Pulmonary Hypertension

Abstract

Introduction: Pulmonary hypertension (PH) is a fatal disease lacking effective treatment strategies to prevent its progression or reverse its effects. PH is characterized by vascular remodeling caused by excessive cell proliferation in the vascular layers. Often, pulmonary artery smooth muscle cells (PASMC) are implicated in the proliferative remodeling of the artery. We recently discovered that in PH, PASMC’s highly expressed a pericyte marker, CD13. Previous studies have shown CD13 pathology in cancer. We hypothesized that increased CD13 expression and activation could mediate a phenotype switch from pericytes to proliferative “PASMC like” cells. Methods: In this study, we used rats with a mutation in NFU1G206C, which spontaneously develop PH with severe vascular remodeling. We also used isolated PASMC from PH patients. We used whole lung single cell transcriptomics to uncover the phenotypes of various lung cells. Results: Pericytes of NFU1 rats showed a significant increase in CD13. Additionally, we found a 40-fold increase of CD13 in NFU1 PASMC. scRNA transcriptomics revealed a high similarity of PASMCs with pericytes in the NFU1 rats. Conversely, we also observed that pericytes of NFU1 rats highly expressed canonical SMC markers like SMMHC and CNN3. CellChat analysis revealed pericyte dysfunction with decreased interaction strength and interaction numbers with endothelial cells (ECs). Correspondingly, confocal imaging revealed a severe decrease in pericyte-EC association and a greater coverage area by pericytes in the NFU1 lungs. Treatment of NFU1 rats with a peptide blocking CD13 signaling (B-CD13) significantly attenuated right ventricular systolic pressure, Fulton index and vascular remodeling. Excitingly, treating isolated PASMC from PH patients and NFU1 rats with B-CD13 reverted the high proliferation rates back to control, indicating the pathological role of CD13 in cell proliferation. scRNA analysis of rat lungs treated with B-CD13 showed improvement in pericyte- EC interaction numbers and interaction strength, indicating that CD13 could play an important role in the migratory and proliferative switch of pericytes. Conclusion: Targeting CD13 signaling is a novel strategy to potentially reverse vascular remodeling in PH.