Preservation of microvascular barrier function requires CD31 receptor-induced metabolic reprogramming

Abstract

Endothelial barrier (EB) breaching is a frequent event during inflammation, and it is followed by the rapid recovery of microvascular integrity. The molecular mechanisms of EB recovery are poorly understood. Triggering of MHC molecules by migrating T-cells is a minimal signal capable of inducing endothelial contraction and transient microvascular leakage. Using this model, we show that EB recovery requires a CD31 receptor-induced, robust glycolytic response sustaining junction re-annealing. Mechanistically, this response involves srchomology phosphatase activation leading to Akt-mediated nuclear exclusion of FoxO1 and concomitant β-catenin translocation to the nucleus, collectively leading to cMyc transcription. CD31 signals also sustain mitochondrial respiration, however this pathway does not contribute to junction remodeling. We further show that pathologic microvascular leakage in CD31-deficient mice can be corrected by enhancing the glycolytic flux via pharmacological Akt or AMPK activation, thus providing a molecular platform for the therapeutic control of EB response.

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“…The effects of endothelial cell lining are also supported by the glycocalyx that controls hemostasis, leukocyte, and platelet adhesion, the transmission of shear stress to the endothelium, and anti‐inflammatory defenses. A disruption of this system may occur during sepsis and result in organ dysfunction, mainly affecting the hemostatic, pulmonary, kidney, and liver systems 9,28 . Whether these alterations in endothelial cell lining is adaptive or maladaptive depends on both disease extension and time from disease onset.…”

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“… 75 This observation has relevance for therapeutic control of angiogenesis in tissue repair and cancer. Other key studies coupled metabolism to the regulation of EC barrier function, 76 , 77 linked exercise with NADPH oxidase 4 (NOX4)-dependent endothelial function, 78 and found catabolism of adenosine driving VSMC proliferation. 79 EC junctions are highly dynamic structures that open and re-anneal in response to specific signals and are disrupted in many vascular diseases.…”

“…Montagne et al 76 found that dysfunction of EC junctions (blood–brain-barrier; BBB) in Alzheimer’s disease is associated with specific allelic forms of apolipoprotein E (ApoE), thereby providing a mechanism linking cholesterol transport with BBB integrity. In addition, Cheung et al 77 demonstrated that EC junction dynamics are also controlled by glycolysis which drives the reannealing process, suggesting a novel mechanism for therapeutic control of endothelial barrier function.…”

Mechanisms of Endothelial Regeneration and Vascular Repair and Their Application to Regenerative Medicine

“…CD31 deficiency has been associated with excessive vascular leakage following endothelial injury induced by histamine, thrombin, and LPS-induced endotoxemia. Employing the MHC activation-induced endothelial barrier disruption model, Cheung et al show that endothelial barrier recovery requires a CD31-induced glycolytic response which sustains endothelial AJ re-assembly 60 . The metabolic reprogramming requires SHP1/2 activation leading to Akt-mediated nuclear exclusion of FoxO1 and concomitant β-catenin translocation to the nucleus and thus induce cMyc transcription.…”

“…The metabolism of ECs in diseased vasculature is markedly aberrant, given that cell proliferation and endothelial junction re-annealing are metabolically demanding processes that requires substantial energy and biomass 60 , 88 . Characterization of EC metabolism in regenerating endothelium is appealing, which could reveal novel reparative pathways and facilitate the targeting of endothelial metabolism in endothelial regeneration and vascular repair 89 .…”