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Am J Pathol. 2015 Jan;185(1):69-84. doi: 10.1016/j.ajpath.2014.09.013. Epub 2014 Nov 6.

Activation of the Wnt/planar cell polarity pathway is required for pericyte recruitment during pulmonary angiogenesis.

Author information

1
Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California; Stanford Cardiovascular Institute, Stanford University, Stanford, California.
2
Division of Endocrinology, Gerontology & Metabolism, Stanford University, Stanford, California.
3
Stanford Cardiovascular Institute, Stanford University, Stanford, California; VA Palo Alto Health Care System, Stanford University, Stanford, California; Department of Cardiothoracic Surgery, Stanford University, Stanford, California.
4
Stanford Cardiovascular Institute, Stanford University, Stanford, California; VA Palo Alto Health Care System, Stanford University, Stanford, California.
5
Department of Pathology, Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, California.
6
Department of Pediatrics, Stanford University School of Medicine, Stanford, California.
7
Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, California; Stanford Cardiovascular Institute, Stanford University, Stanford, California. Electronic address: vdejesus@stanford.edu.

Abstract

Pericytes are perivascular cells localized to capillaries that promote vessel maturation, and their absence can contribute to vessel loss. Whether impaired endothelial-pericyte interaction contributes to small vessel loss in pulmonary arterial hypertension (PAH) is unclear. Using 3G5-specific, immunoglobulin G-coated magnetic beads, we isolated pericytes from the lungs of healthy subjects and PAH patients, followed by lineage validation. PAH pericytes seeded with healthy pulmonary microvascular endothelial cells failed to associate with endothelial tubes, resulting in smaller vascular networks compared to those with healthy pericytes. After the demonstration of abnormal polarization toward 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. PAH pericytes had reduced expression of frizzled 7 (Fzd7) and cdc42, genes crucial for Wnt/PCP activation. With simultaneous knockdown of Fzd7 and cdc42 in healthy pericytes in vitro and in a murine model of angiogenesis, motility and polarization toward pulmonary microvascular endothelial cells were reduced, whereas with restoration of both genes in PAH pericytes, endothelial-pericyte association was improved, with larger vascular networks. These studies suggest that the motility and polarity of pericytes during pulmonary angiogenesis are regulated by Wnt/PCP activation, which can be targeted to prevent vessel loss in PAH.

PMID:
25447046
PMCID:
PMC4278244
DOI:
10.1016/j.ajpath.2014.09.013
[Indexed for MEDLINE]
Free PMC Article

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