We previously demonstrated that endothelial secretion of Wnt5a, a ligand in the Wnt signaling pathway, promotes lung vessel maturation by recruiting pericytes through activation of the planar cell polarity (PCP) pathway. This process requires Wnt interaction with a cell surface receptor complex that includes ROR2, a tyrosine kinase membrane receptor. Following vascular injury in the lung, Wnt7a plays a critical role in coordinating angiogenesis, the repair of damaged vessels. This involves extensive migration and proliferation of pulmonary microvascular endothelial cells (PMVECs). Wnt7a enhances VEGF signaling in lung PMVECs, and its loss is associated with a weakened VEGF-A mediated angiogenic response, contributing to small vessel loss. By exploring how Wnt7a and its receptors interact to regulate new vessel formation, we aim to gain deeper insight into the mechanisms of vascular remodeling in PAH.

Right ventricular (RV) remodeling in pulmonary hypertension leads to significant changes in the heart, including vascular impairment, cardiomyocyte dysfunction, and fibrosis. While adaptive remodeling preserves capillary density and supports survival, maladaptive remodeling results in vascular rarefaction, fibrosis, and ultimately RV failure. Although Wnt signaling has been well-studied in left ventricular repair, its role in right ventricular hypertrophy remains less understood. Our research explores how angiogenesis, regulated by interactions between cardiac endothelial cells (CECs) and pericytes (PCs), contributes to maintaining RV vascularization. We hypothesize that Wnt signaling in cardiac cells is essential for adapting to increased pressure load and may help prevent heart failure. By studying healthy, adaptive, and maladaptive RV tissues, we aim to define how Wnt5a/ROR2 signaling influences angiogenic responses, with the long-term goal of identifying therapeutic targets to prevent RV failure in PAH.

Pulmonary arterial hypertension (PAH) is characterized by the progressive loss and impaired regeneration of pulmonary microvessels. A key step in forming functional vascular networks is the coating of endothelial tubes with pericytes-highly specialized mural cells that interact with endothelial cells to provide structural support and promote vessel maturation during angiogenesis. Our research shows that disrupted endothelial-pericyte (EC-PC) interactions during vascular network formation are linked to small vessel loss in PAH. We have found that exosomes derived from PAH pericytes, containing specific miRNAs and protein cargo, inhibit angiogenesis in endothelial cells and interfere wi th pericyte recruitment to blood vessels.Ongoing studies aim to identify molecular targets that regulate EC-PC interactions and may offer new therapeutic strategies for PAH. We are also investigating how restoring physiological signaling levels can reverse PAH pericyte-induced dysfunction in healthy pulmonary microvascular endothelial cells (PMVECs).

Understanding the cellular and molecular mechanisms that regulate inflammation and immune responses in the pulmonary vasculature is critical, as it may enable the development of PAH-specific immunotherapies. This project introduces a novel concept by identifying LITAF as a key driver of inflammatory signaling in pericytes. Our model links LITAF to the transcription and secretion of pro-inflammatory cytokines, offering new insights into its role in pulmonary inflammation. We are also exploring how LITAF, via exosomes and extracellular vesicles, may help mitigate PAH pericyte-induced dysfunction in pulmonary microvascular endothelial cells (PMVECs). Additionally, we aim to understand the mechanisms connecting LITAF to pericyte-specific immune responses, and whether restoring its expression enables pericytes to better support angiogenesis. Using both in vivo and in vitro models of LITAF overexpression and knockout, we are working to establish a platform for testing LITAF-based therapeutic strategies, potentially opening new avenues for PAH treatment.