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We explored the extent to which endothelial<jats:styled-content style=\"fixed-case\">PKR<\/jats:styled-content>1 contributes to expansion of capillary network and the transcapillary passage of insulin into the heart, kidney, and adipose tissues, regulating organ functions and metabolism in a specific mice model.<\/jats:p><\/jats:sec><jats:sec xml:lang=\"en\"><jats:title>Methods and Results<\/jats:title><jats:p xml:lang=\"en\">By combining cellular studies and studies in endothelium\u2010specific loss\u2010of\u2010function mouse model (ec\u2010PKR1<jats:sup>\u2212\/\u2212<\/jats:sup>), we showed that a genetically induced<jats:styled-content style=\"fixed-case\">PKR<\/jats:styled-content>1 loss in the endothelial cells causes the impaired capillary formation and transendothelial insulin delivery, leading to insulin resistance and cardiovascular and renal disorders. Impaired insulin delivery in endothelial cells accompanied with defective expression and activation of endothelial nitric oxide synthase in the<jats:italic>ec\u2010PKR1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>aorta, consequently diminishing endothelium\u2010dependent relaxation. Despite having a lean body phenotype, ec\u2010<jats:styled-content style=\"fixed-case\">PKR<\/jats:styled-content>1<jats:sup>\u2212\/\u2212<\/jats:sup>mice exhibited polyphagia, polydipsia, polyurinemia, and hyperinsulinemia, which are reminiscent of human lipodystrophy. High plasma<jats:styled-content style=\"fixed-case\">free fatty acid levels<\/jats:styled-content>and low leptin levels further contribute to the development of insulin resistance at the later age. Peripheral insulin resistance and ectopic lipid accumulation in mutant skeletal muscle, heart, and kidneys were accompanied by impaired insulin\u2010mediated Akt signaling in these organs. The<jats:italic>ec\u2010PKR1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice displayed myocardial fibrosis, low levels of capillary formation, and high rates of apoptosis, leading to diastolic dysfunction. Compact fibrotic glomeruli and high levels of phosphate excretion were found in mutant kidneys. PKR1 restoration in<jats:italic>ec\u2010PKR1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice reversed the decrease in capillary recruitment and insulin uptake and improved heart and kidney function and insulin resistance.<\/jats:p><\/jats:sec><jats:sec xml:lang=\"en\"><jats:title>Conclusions<\/jats:title><jats:p xml:lang=\"en\">We show a novel role for endothelial<jats:styled-content style=\"fixed-case\">PKR<\/jats:styled-content>1 signaling in cardiac, renal, and metabolic functions by regulating transendothelial insulin uptake and endothelial cell proliferation. Targeting endothelial<jats:styled-content style=\"fixed-case\">PKR<\/jats:styled-content>1 may serve as a therapeutic strategy for ameliorating these disorders.<\/jats:p><\/jats:sec>","DOI":"10.1161\/jaha.113.000411","type":"journal-article","created":{"date-parts":[[2013,10,24]],"date-time":"2013-10-24T03:08:36Z","timestamp":1382584116000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":39,"title":["Prokineticin Receptor\u20101 Is a New Regulator of Endothelial Insulin Uptake and Capillary Formation to Control Insulin Sensitivity and Cardiovascular and Kidney Functions"],"prefix":"10.1161","volume":"2","author":[{"given":"Mojdeh","family":"Dormishian","sequence":"first","affiliation":[{"name":"CNRS, Universit\u00e9 de Strasbourg, UMR7242, Ecole Sup\u00e9rieure de Biotechnologie de Strasbourg, and Medalis\/Labex, Drug Discovery Center, Illkirch, 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