LAUSR

Vascular complications are major causes of morbidity and mortality in diabetic patients. Recently, our group identified a novel purinergic signaling pathway involving the AKAP5/P2Y11/AC5/PKA/CaV1.2 protein network in arterial myocytes that is activated upon diabetic hyperglycemia leading to vasoconstriction. This purinergic complex is activated by the release of nucleotides (e.g. ATP) to the extracellular space in response to hyperglycemic conditions. Pannexin 1 (Panx1) is a channel that mediates ATP efflux, thus inducing purinergic signaling activation. In this study, we hypothesize that Panx1 is a critical regulator mediating ATP release and increasing cAMP synthesis, CaV1.2 potentiation, and vasoconstriction upon diabetic hyperglycemia. Consistent with this hypothesis, we found that elevated glucose (HG) induced an elevation in extracellular ATP concentrations, and this was reduced in the presence of the Panx1 inhibitor spironolactone (spiro). Panx1 was found in complex with AKAP5, P2Y11, AC5, PKA, and CaV1.2 in arterial myocytes. This protein complex was strengthened upon HG treatment, and spiro prevented this effect. Spiro and genetic ablation of smooth muscle Panx1 (iPanx1sm -/-) blocked cAMP production, CaV1.2 potentiation, sustained vasoconstriction, and in vivo elevations in cerebral artery myogenic tone and reduced blood flow in response to HG. In a mouse model of type 1 diabetes (e.g. STZ), the increased CaV1.2 potentiation and enhanced myogenic tone were prevented in arterial myocytes and arteries from iPanx1sm -/- mice. Altogether, these data suggest that Panx1 is part of the AKAP5/P2Y11/AC5/PKA/CaV1.2 signaling module in arterial myocytes. This Panx1-led complex modulates CaV1.2 activity and vascular reactivity in response to diabetic hyperglycemia. Thus, Panx1 could be a new therapeutic target to treat vascular complications during diabetes. This work was supported by NIH grants R01HL149127, R01HL121059, and R01HL161872 (to MFN). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.