Abstract 14503: Loss of Wnt5a Disrupts Endothelial-Pericyte Interaction During Pulmonary Angiogenesis
Introduction: Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by impaired angiogenesis, progressive small vessel loss and occlusive vasculopathy. Pericyte recruitment and establishment of endothelial-pericyte interactions is a critical event to ensure structural integrity and proper function of new vessels and at the center of this is Wnt/PCP based on our studies.
Hypothesis: Given our published evidence for reduced Wnt/PCP activation in PAH pericytes, we hypothesized that altered expression of Wnt ligands and/or receptors was responsible for the abnormal PAH pericytes response to ECs.
Methods: we co-cultured healthy pericytes with healthy ECs for 24 hours followed by cell sorting and Taqman qPCR profiling of Wnt genes. Expression Wnt5a were validated in histological sections and purified lung using Taqman qPCR, western blot and immunofluorescence. We have generated a novel conditional knockout(cKO) Wnt5a mouse model only in endothelium to determine if loss of Wnt5a is associated with pulmonary hypertension and reduced angiogenesis.
Results: 1) In contrast to healthy donor, an increase Wnt5a gene expression in ECs was found after co-culture with pericytes. In contrast, reduced Wnt5a expression in the endothelium of obliterative pulmonary lesions was found in PAH lungs. Given low gene expression of Wnt5a in PAH ECs, we sought to look for epigenetic repression. 2) Wnt5a was secreted in exosome vesicles by ECs during pericytes recruitment. 3) Wnt5a cKO mice developed and persist PH and right ventricular hypertrophy after exposed to 3 weeks of hypoxia(10%O2) followed by 3 weeks of reoxygenation. In addition, their lungs had reduced number of distal vessels but increased number of muscularized and remodeled vessels.
Conclusions: We demonstrate the novel role of Wnt5a that regulates communication of EC and pericytes during pulmonary angiogenesis which appears disrupted in PAH and correlates with small vessel loss. This study will also produce a blueprint for how we should approach the development of novel therapeutics that target Wnt5a signaling in the pulmonary circulation.
Author Disclosures: K. Yuan: None. M. Orcholski: None. E. Shamskhou: None. M. Discipulo: None. V. de Jesus Perez: None.
- © 2016 by American Heart Association, Inc.