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  • Mural Cell SDF1 Signaling is Associated with the Pathogenesis of Pulmonary Arterial Hypertension. American journal of respiratory cell and molecular biology Yuan, K., Liu, Y., Zhang, Y., Nathan, A., Tian, W., Yu, J., Sweatt, A. J., Condon, D., Chakraborty, A., Agarwal, S., Auer, N., Zhang, S., Wu, J. C., Zamanian, R. T., Nicolls, M. R., de Jesus Perez, V. A. 2020

    Abstract

    Pulmonary artery smooth muscle cells (PASMCs) and pericytes are NG2+ mural cells that provide structural support to pulmonary arteries and capillaries. In pulmonary arterial hypertension (PAH), both mural cell types contribute to PA muscularization but whether similar mechanisms are responsible for their behavior is unknown.RNA-Seq was used to compare the gene profile of pericytes and PASMCs from PAH and healthy lungs. NG2-Cre-ER mice were used to generate NG2-selective reporter mice (NG2tdT) for cell lineage identification and tamoxifen-inducible mice for NG2-selective SDF1 knockout (SDF1NG2-KO).Hierarchical clustering of RNA-seq data demonstrated that the genetic profile of PAH pericytes and PASMCs is highly similar. Cellular lineage staining studies on NG2tdT mice in chronic hypoxia showed that similar to PAH, tdT+ cells accumulate in muscularized microvessels and demonstrate significant upregulation of SDF1, a chemokine involved in chemotaxis and angiogenesis. Compared to controls, SDF1NG2-KO mice in chronic hypoxia had reduced muscularization and lower abundance of NG2+ cells around microvessels. SDF1 stimulation in healthy pericytes induced greater contractility and impaired their capacity to establish endothelial-pericyte communications. In contrast, SDF1 knockdown reduced PAH pericyte contractility and improved their capacity to associate with vascular tubes in co-culture.SDF1 is upregulated in NG2+ mural cells and is associated with PA muscularization. Targeting SDF1 could help prevent and/or reverse muscularization in PAH.

    View details for DOI 10.1165/rcmb.2019-0401OC

    View details for PubMedID 32084325

  • The stressed optic nerve: gliopathy in hypoxic injury and potential for therapy Mesentier-Louro, L., Camargo, A., Shariati, A., Nathan, A., Dalal, R., Kumar, V., Dardet, M. E., Perez, V., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019
  • Hydrogel-based delivery of Il-10 improves treatment of bleomycin-induced lung fibrosis in mice BIOMATERIALS Shamskhou, E. A., Kratochvil, M. J., Orcholski, M. E., Nagy, N., Kaber, G., Steen, E., Balaji, S., Yuan, K., Keswani, S., Danielson, B., Gao, M., Medina, C., Nathan, A., Chakraborty, A., Bollyky, P. L., Perez, V. 2019; 203: 52?62
  • Loss of Endothelium-Derived Wnt5a Is Associated With Reduced Pericyte Recruitment and Small Vessel Loss in Pulmonary Arterial Hypertension CIRCULATION Yuan, K., Shamskhou, E. A., Orcholski, M. E., Nathan, A., Reddy, S., Honda, H., Mani, V., Zeng, Y., Ozen, M. O., Wang, L., Demirci, U., Tian, W., Nicolls, M. R., Perez, V. 2019; 139 (14): 1710?24
  • Loss of Endothelial Derived WNT5A is Associated with Reduced Pericyte Recruitment and Small Vessel Loss in Pulmonary Arterial Hypertension. Circulation Yuan, K., Shamskhou, E. A., Orcholski, M. E., Nathan, A., Reddy, S., Honda, H., Mani, V., Zeng, Y., Ozen, M. O., Wang, L., Demirci, U., Tian, W., Nicolls, M. R., de Jesus Perez, V. A. 2018

    Abstract

    Pulmonary arterial hypertension (PAH) is a life-threatening disorder of the pulmonary circulation associated with loss and impaired regeneration of microvessels. Reduced pericyte coverage of pulmonary microvessels is a pathological feature of PAH and is partly due to the inability of pericytes to respond to signaling cues from neighboring pulmonary microvascular endothelial cells (PMVECs). We have shown that activation of the Wnt/PCP pathway is required for pericyte recruitment but whether production and release of specific Wnt ligands by PMVECs is responsible for Wnt/PCP activation in pericytes is unknown.Isolation of pericytes and PMVECs from healthy donor and PAH lungs was carried out using 3G5 or CD31 antibody conjugated magnetic beads. Wnt expression profile of PMVECs was documented via qPCR using a Wnt primer library. Exosome purification from PMVEC media was carried out using the ExoTIC device. Hemodynamic profile, right ventricular function and pulmonary vascular morphometry were obtained in a conditional endothelial specific Wnt5a knockout ( Wnt5aECKO) mouse model under normoxia, chronic hypoxia and hypoxia recovery.Quantification of Wnt ligand expression in healthy PMVECs co-cultured with pericytes demonstrated a 35-fold increase in Wnt5a, a known Wnt/PCP ligand. This Wnt5a spike was not seen in PAH PMVECs, which correlated with inability to recruit pericytes in matrigel co-culture assays. Exosomes purified from media demonstrated an increase in Wnt5a content when healthy PMVECs were co-cultured with pericytes, a finding that was not observed in exosomes of PAH PMVECs. Furthermore, the addition of either recombinant Wnt5a or purified healthy PMVEC exosomes increased pericyte recruitment to PAH PMVECs in co-culture studies. While no differences were noted in normoxia and chronic hypoxia, Wnt5aECKO mice demonstrated persistent pulmonary hypertension and right ventricular failure four weeks after recovery from chronic hypoxia, which correlated with significant reduction, muscularization and decreased pericyte coverage of microvessels.We identify Wnt5a as a key mediator for the establishment of pulmonary endothelial-pericyte interactions and its loss could contribute to PAH by reducing the viability of newly formed vessels. We speculate that therapies that mimic or restore Wnt5a production could help prevent loss of small vessels in PAH.

    View details for PubMedID 30586764

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