Changes in the vessel's molecular identity after vascular surgery correspond to structural changes that depend on the host's postsurgical environment. Regulation of vascular identity and the underlying molecular mechanisms may allow new therapeutic approaches to improve vascular surgical procedures.

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Normal healing after aortic patch angioplasty is associated with increased TGF-β1 signaling, and recruitment of smad2 signaling may limit pseudoaneurysm formation; loss of TGF-β1 signaling is associated with the formation of large pseudoaneurysms. Enhancement of TGF-β1 signaling may be a potential mechanism to limit pseudoaneurysm formation after vascular intervention.

Objective: Arteriovenous fistulae (AVF) are the optimal conduit for hemodialysis access but have high rates of primary maturation failure. Successful AVF maturation requires wall thickening with deposition of ECM (extracellular matrix) including collagen and fibronectin, as well as lumen dilation. TAK1 (TGFβ [transforming growth factor-beta]–activated kinase 1) is a mediator of noncanonical TGFβ signaling and plays crucial roles in regulation of ECM production and deposition; therefore, we hypothesized that TAK1 regulates wall thickening and lumen dilation during AVF maturation. Approach and Results: In both human and mouse AVF, immunoreactivity of TAK1, JNK (c-Jun N-terminal kinase), p38, collagen 1, and fibronectin was significantly increased compared with control veins. Manipulation of TAK1 in vivo altered AVF wall thickening and luminal diameter; reduced TAK1 function was associated with reduced thickness and smaller diameter, whereas activation of TAK1 function was associated with increased thickness and larger diameter. Arterial magnitudes of laminar shear stress (20 dyne/cm 2 ) activated noncanonical TGFβ signaling including TAK1 phosphorylation in mouse endothelial cells. Conclusions: TAK1 is increased in AVF, and TAK1 manipulation in a mouse AVF model regulates AVF thickness and diameter. Targeting noncanonical TGFβ signaling such as TAK1 might be a novel therapeutic approach to improve AVF maturation.

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Vascular remodeling within the uterus immediately before and during early pregnancy increases blood flow to the fetus and prevents the development of gestational hypertension. Tissue resident Natural Killer (trNK) cells secrete pro-angiogenic growth factors but are insufficient for uterine artery (UtA) remodeling in the absence of conventional NK (cNK) cells. Matrix metalloproteinase-9 (MMP9) is activated in acidic environments to promote UtA remodeling. We have previously shown that ATPase a2V plays a role in regulating the function of cNK cell during pregnancy. We studied the effect of a2V deletion on uterine cNK cell populations and pregnancy outcomes in VavCrea2Vfl/fl mice, where a2V is conditionally deleted in hematopoietic stem cells. cNK cells were reduced but trNK cells were retained in implantation sites at gestational day 9.5, and UtA remodeling was inhibited despite no differences in concentrations of pro-angiogenic growth factors. The ratio of pro-MMP9 to total was significantly elevated in VavCrea2Vfl/fl mice, and MMP9 activity was significantly reduced. pH of implantation sites was significantly elevated in VavCrea2Vfl/fl mice. We concluded that the role of cNK cells in the uterus is to acidify the extracellular matrix (ECM) using a2V, which activates MMP9 to degrade the ECM, release bound pro-angiogenic growth factors, and contribute to UtA remodeling. Our results are significant to the understanding of development of gestational hypertension.

Tumor-associated angiogenesis is accompanied by immunosuppression mediated by tumor cells and the immune microenvironment. Similarly, embryo implantation in the uterus requires both angiogenesis and immunosuppression. Uterine natural killer (NK) cells promote immune tolerance for the allogenic invasion of the embryo during pregnancy. In these studies, we explore the mechanism of NK cell-mediated vascular remodeling. RNA sequencing demonstrates a subpopulation of uterine NK cells that are enriched for proangiogenic genes in the uterus during pregnancy. Ephrin-B2 is a receptor tyrosine kinase well known for promoting angiogenesis in cancer, however, the mechanism for ephrin-B2-mediated angiogenesis in the uterus is not known. NK cells were isolated from the uterus and spleen of mice. Isolated NK cells were characterized for the expression of ephrin-B2 by immunofluorescence and flow cytometry. We show that uterine, but not splenic, NK cells express ephrin-B2. Because uterine NK cells also mediate immunosuppression, uterine NK cells were probed for expression of cytotoxicity markers. Cytotoxic marker CD27 is significantly upregulated in conventional NK cells, but not tissue-resident NK cells. Our data show that tissue resident uterine NK cells express pro-angiogenic marker ephrin-B2 and that these cells are not cytotoxic. This describes a previously unsuspected function for NK cells.