Abstract 9649: Impaired Pulmonary Angiogenesis in Idiopathic Pulmonary Arterial Hypertension is Linked to Abnormal Pericyte Function and Reduced Endothelial-pericyte Interactions
Idiopathic pulmonary arterial hypertension (IPAH) is associated with progressive small vessel loss and impaired vascular regeneration. Pericytes are highly specialized vascular cells that directly interact with endothelial cells to provide mural support and promote small vessel maturation and survival. While it is possible that abnormalities in the initiation and maintenance of endothelial-pericyte interactions could contribute to small vessel loss in IPAH, little is known about the role of pericytes in the pulmonary. To circumvent this limitation, we have developed a novel method to purify pericytes from the lungs of failed donors and IPAH patients obtained through the Pulmonary Hypertension Breakthrough Initiative (PHBI). Healthy pulmonary artery endothelial cells (PAECs) on matrigel demonstrated reduced vascular tube formation in the presence of IPAH pericytes compared to control (P<0.0001). The vast majority of IPAH pericytes not only failed to reach and attach themselves to endothelial tubes but also had abnormalities in adhesion, motility and cell polarity. Disruption of Wnt/planar cell polarity (PCP) can contribute to both PAEC loss and impaired tube formation in pulmonary angiogenesis. Given the discrete adhesion, motility and polarity defects of IPAH pericytes, disruption in Wnt/PCP pathway could also contribute to the phenotypic differences observed between healthy and IPAH pericytes. To begin exploring this possibility, gene expression pattern of Wnt ligands and receptors in healthy pericytes and PAECs alone and after co-culture were characterized by qRT-PCR. Compared to single cultures, Wnt5a gene expression was increased in PAECs while an increase in both Vangl1 and ROR2 were seen in pericytes. PAECs with Wnt5a-knockout cannot recruit healthy pericytes in would healing assay as well as in 3D collagen gels. Given that Wnt5a is a known ligand of Wnt/PCP that triggers intracellular signaling through the surface receptors Vangl1 and ROR2 receptors, these preliminary studies strongly suggest that impaired pericyte recruitment to pulmonary vessels resulting from disruption of Wnt/PCP signaling may result in progressive vessel loss and impaired regeneration in IPAH.
- © 2012 by American Heart Association, Inc.