Vascular wound repair is controlled by a complex interaction between local vascular cells and circulating immune and non-immune cells. Recently, the classic dogma of a predominantly local response to injury has been challenged by the identification of circulating vascular progenitor cells. The role of these vascular progenitor cells in vascular regeneration and their interaction with local vascular cells and infiltrating immune cells is poorly understood. My laboratory has undertaken a number of approaches to understand how these cells contribute to the overall vascular injury response and how they might ultimately be therapeutically manipulated. We studied events immediately following arterial injury and identified an acute STAT3- and NF-B (p65 subunit)-dependent upregulation of RANTES production by medial VSMCs, leading to early T cell and macrophage recruitment - processes also under the higher-order regulation of p21Cip1. Unique to VSMCs, RANTES production was initiated by TNF but not IL-6/gp130, and was dependent on binding of a p65-STAT3 complex to NF-B binding sites within the RANTES promoter, with shRNA knockdown of either STAT3 or p65 markedly attenuating RANTES production. In vivo, acute NF-B and STAT3 activation in medial VSMCs was identified, with acute RANTES production after injury significantly reduced in TNF-/- mice compared to controls. Finally, we generated mice with smooth muscle cell-specific conditional STAT3 knockout (STAT3fl/fl;SM22-Cre) and confirmed the STAT3-dependence of acute RANTES production by VSMCs. Together, these observations unify inflammatory events after vascular injury, demonstrating that VSMCs orchestrate the arterial inflammatory response program via acute RANTES production and subsequent inflammatory cell recruitment. Veins grafted into an arterial environment undergo vascular remodeling, a complex process of major clinical importance. Using lineage tracing experiments, we provide unprecedented evidence that cells of endothelial origin from the vein graft contribute to mesenchymal cellularity; during neointimal formation. In murine jugular veins grafted to femoral arteries, we found that endothelial cells lose their nascent markers and over time gain smooth muscle cell markers, indicative of endothelial to mesenchymal transition (EndoMT). This process is dependent on TGF- signaling, with early Smad activation. Antagonism of TGF- signaling by TGF- neutralizing antibody, siRNA-mediated Smad3 knockdown, or Smad3 haploinsufficiency resulted in decreased EndoMT and favorable vascular remodeling. Hence, we have identified EndoMT as a novel and pivotal mechanism underlying the stenosis-producing neointimal overgrowth of vein grafts, implying a potential a new therapeutic target to prevent vein graft pathology.

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Support Year
7
Fiscal Year
2016
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Indirect Cost
Name
U.S. National Heart Lung and Blood Inst
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Evrard, Solene M; Lecce, Laura; Michelis, Katherine C et al. (2017) Corrigendum: Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability. Nat Commun 8:14710
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Negro, Alejandra; Boehm, Manfred (2014) Cardiomyocyte maturation: It takes a village to raise a kid. J Mol Cell Cardiol 74:193-5
Cooley, Brian C; Nevado, Jose; Mellad, Jason et al. (2014) TGF-? signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Sci Transl Med 6:227ra34
Michelis, Katherine C; Boehm, Manfred; Kovacic, Jason C (2014) New vessel formation in the context of cardiomyocyte regeneration--the role and importance of an adequate perfusing vasculature. Stem Cell Res 13:666-82
Wood, Katherine C; Cortese-Krott, Miriam M; Kovacic, Jason C et al. (2013) Circulating blood endothelial nitric oxide synthase contributes to the regulation of systemic blood pressure and nitrite homeostasis. Arterioscler Thromb Vasc Biol 33:1861-71

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