Abstract 16306: Activation of the Wnt/Planar Cell Polarity Pathway is Required for Pericyte Recruitment During Pulmonary Angiogenesis
Rationale: Pericytes are perivascular cells localized to capillaries that promote vessel maturation and their absence can contribute to vessel loss. Whether impaired pericyte interaction with endothelial cells contributes to small vessel loss in pulmonary arterial hypertension (PAH) is unclear.
Objective: To measure the ability of PAH pericytes to associate with pulmonary microvascular endothelial cells (PMVECs) in vitro and in vivo.
Methods and Results: Using 3G5 specific IgG-coated magnetic beads, we isolated pericytes from lungs of healthy and PAH patients followed by lineage validation. When seeded with healthy PMVECs, PAH pericytes failed to associate with endothelial tubes, resulting in smaller vascular networks compared to those seen with healthy pericytes. Following demonstration of abnormal polarization towards endothelium via live imaging and wound-healing studies, we screened PAH pericytes for abnormalities in the Wnt/planar cell polarity (PCP) pathway, which has been shown to regulate cell motility and polarity in the pulmonary vasculature. We found that PAH pericytes have reduced expression of frizzled 7 (Fzd7) and cdc42, two genes critical for Wnt/PCP activation. Simultaneous knockdown of Fzd7 and cdc42 in healthy pericytes resulted in reduced motility and polarization towards PMVECs both in vitro and in a murine model of angiogenesis, whereas restoration of both genes in PAH pericytes resulted in improved endothelial-pericyte association and larger vascular networks.
Conclusions: These studies suggest that the motility and polarity of pericytes during pulmonary angiogenesis is regulated by Wnt/PCP activation. Therapies targeting Wnt/PCP in pericytes could help prevent vessel loss in PAH.
Author Disclosures: K. Yuan: None. M. Orcholski: None. C. Panaroni: None. N. Huang: None. X. Jiang: None. W. Tian: None. E. Vladar: None. M. Nicolls: None. J. Wu: None. V. de Jesus Perez: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.