Impaired endothelial cell (EC)–mediated angiogenesis contributes to critical limb ischemia in diabetic patients. The sonic hedgehog (SHH) pathway participates in angiogenesis but is repressed in hyperglycemia by obscure mechanisms. We investigated the orphan G protein–coupled receptor GPR39 on SHH pathway activation in ECs and ischemia-induced angiogenesis in animals with chronic hyperglycemia. Human aortic ECs from healthy and type 2 diabetic (T2D) donors were cultured in vitro. GPR39 mRNA expression was significantly elevated in T2D. The EC proliferation, migration, and tube formation were attenuated by adenovirus-mediated GPR39 overexpression (Ad-GPR39) or GPR39 agonist TC-G-1008 in vitro. The production of proangiogenic factors was reduced by Ad-GPR39. Conversely, human ECs transfected with GPR39 siRNA or the mouse aortic ECs isolated from GPR39 global knockout (GPR39 KO ) mice displayed enhanced migration and proliferation compared with their respective controls. GPR39 suppressed the basal and ligand-dependent activation of the SHH effector GLI1, leading to attenuated EC migration. Coimmunoprecipitation revealed that the GPR39 direct binding of the suppressor of fused (SUFU), the SHH pathway endogenous inhibitor, may achieve this. Furthermore, in ECs with GPR39 knockdown, the robust GLI1 activation and EC migration were abolished by SUFU overexpression. In a chronic diabetic model of diet-induced obesity (DIO) and low-dose streptozotocin (STZ)-induced hyperglycemia, the GPR39 KO mice demonstrated a faster pace of revascularization from hind limb ischemia and lower incidence of tissue necrosis than GPR39 wild-type (GPR39 WT ) counterparts. These findings have provided a conceptual framework for developing therapeutic tools that ablate or inhibit GPR39 for ischemic tissue repair under metabolic stress.

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Introduction Patients suffering from large or deep wounds caused by traumatic and/or thermal injuries have significantly lower chances of recapitulating lost skin function through natural healing. We tested whether enhanced Unfolded Protein Response (UPR) by expression of a UPR transcriptional activator, X-box binding protein 1 (XBP1), can significantly promote wound repair through stimulating growth factor production and promoting angiogenesis. Methods and Results In mouse models of a second-degree thermal wound, a full-thickness traumatic wound, and a full-thickness diabetic wound, the topical gene transfer of the activated form of XBP1 (spliced XBP1, XBP1s) can significantly enhance re-epithelialization and increase angiogenesis, leading to rapid, nearly complete wound closure with intact regenerated epidermis and dermis. Over-expression of XBP1s stimulated the transcription of growth factors in fibroblasts critical to proliferation and remodelling during wound repair, including PDGF BB, FGF2, and TGFβ3. Meanwhile, the over-expression of XBP1s boosted the migration and tube formation of dermal microvascular endothelial cells in vitro. Conclusion Our functional and mechanistic investigations of XBP1-mediated regulation of wound healing processes provide novel insights into the previously undermined physiological role of the UPR in skin injuries. The finding opens an avenue to developing potential XBP1-based therapeutic strategies in clinical wound care protocols.