PMID- 36574661 OWN - NLM STAT- MEDLINE DCOM- 20221229 LR - 20230712 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 120 IP - 1 DP - 2023 Jan 3 TI - Inhibition of GPR39 restores defects in endothelial cell-mediated neovascularization under the duress of chronic hyperglycemia: Evidence for regulatory roles of the sonic hedgehog signaling axis. PG - e2208541120 LID - 10.1073/pnas.2208541120 [doi] LID - e2208541120 AB - 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. FAU - Meda Venkata, Sai Pranathi AU - Meda Venkata SP AUID- ORCID: 0000-0002-1771-4806 AD - Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201. FAU - Li, Hainan AU - Li H AUID- ORCID: 0000-0002-2967-8021 AD - Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201. FAU - Xu, Liping AU - Xu L AD - Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201. FAU - Koh, Jia Yi AU - Koh JY AD - Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201. FAU - Nguyen, Huong AU - Nguyen H AD - Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201. FAU - Minjares, Morgan AU - Minjares M AD - Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201. FAU - Li, Chunying AU - Li C AUID- ORCID: 0000-0003-4040-5689 AD - Center of Molecular and Translational Medicine and the Institute of Biomedical Sciences, Georgia State University, Atlanta, GA 30303. FAU - Kowluru, Anjaneyulu AU - Kowluru A AUID- ORCID: 0000-0003-1700-0077 AD - Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201. AD - John D. Dingell Department of Veterans Affairs Medical Center, Detroit, MI 48201. FAU - Milligan, Graeme AU - Milligan G AUID- ORCID: 0000-0002-6946-3519 AD - Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom. FAU - Wang, Jie-Mei AU - Wang JM AUID- ORCID: 0000-0002-8723-4410 AD - Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201. AD - Centers for Molecular Medicine and Genetics, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201. LA - eng GR - R01 EY022230/EY/NEI NIH HHS/United States GR - IK6 BX005383/BX/BLRD VA/United States GR - I01 BX004663/BX/BLRD VA/United States GR - P30 DK020572/DK/NIDDK NIH HHS/United States GR - R01 DK109036/DK/NIDDK NIH HHS/United States GR - R01 DK119222/DK/NIDDK NIH HHS/United States GR - T32 GM139807/GM/NIGMS NIH HHS/United States GR - R01 DK128937/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20221227 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Hedgehog Proteins) RN - 0 (Zinc Finger Protein GLI1) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (GPR39 protein, human) RN - 0 (GPR39 protein, mouse) SB - IM CIN - Proc Natl Acad Sci U S A. 2023 Jul 11;120(28):e2308227120. PMID: 37399396 CIN - Proc Natl Acad Sci U S A. 2023 Jul 11;120(28):e2308643120. PMID: 37399406 MH - Humans MH - Mice MH - Animals MH - Hedgehog Proteins/metabolism MH - Zinc Finger Protein GLI1 MH - Cells, Cultured MH - Neovascularization, Physiologic/physiology MH - Endothelial Cells/metabolism MH - Neovascularization, Pathologic MH - Ischemia MH - Receptors, G-Protein-Coupled/genetics MH - *Hyperglycemia/genetics MH - *Diabetes Mellitus, Type 2/genetics PMC - PMC9910611 OTO - NOTNLM OT - G protein-coupled receptor 39 OT - angiogenesis OT - endothelial function OT - hyperglycemia OT - limb ischemia COIS- The authors declare no competing interest. EDAT- 2022/12/28 06:00 MHDA- 2022/12/30 06:00 PMCR- 2022/12/27 CRDT- 2022/12/27 16:22 PHST- 2022/12/27 16:22 [entrez] PHST- 2022/12/28 06:00 [pubmed] PHST- 2022/12/30 06:00 [medline] PHST- 2022/12/27 00:00 [pmc-release] AID - 202208541 [pii] AID - 10.1073/pnas.2208541120 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2208541120. doi: 10.1073/pnas.2208541120. Epub 2022 Dec 27.