Abstract
<jats:p><p dir="ltr">Glucose-dependent insulinotropic polypeptide (GIP) promotes nutrient storage, but its vascular actions in skeletal muscle remain unclear. To determine whether GIP regulates muscle microvascular perfusion - a key determinant of substrate utilization - we examined GIP receptor (GIPR) expression in vascular endothelium and assessed GIP effects in vivo in chow- and high-fat diet (HFD)-fed rats. Overnight-fasted rats received 120-minute infusions of saline or GIP, with or without concurrent insulin or glucagon-like peptide-1 (GLP-1). Immunofluorescence microscopy demonstrated clear GIPR expression in conduit, resistance, and microvascular vessel endothelium. GIP alone did not alter muscle microvascular perfusion in either group but completely abolished insulin- and GLP-1-induced microvascular recruitment. In cultured endothelial cells, GIP dose-dependently increased endothelin-1 secretion and suppressed insulin- or GLP-1-stimulated nitric oxide production. Transcriptomic profiling implicated activation of the GIP-angiotensin II type 1 receptor-endothelin-1 (GIP–AT1R–ET-1) pathway. In conclusion, GIPR is widely expressed in vascular endothelium. While GIP does not independently recruit muscle microvasculature, it antagonizes insulin- and GLP-1-mediated vasodilation, identifying GIP as a conditional regulator of skeletal muscle perfusion and nutrient delivery, consistent with its physiological effect in directing nutrients toward storage depots.</p></jats:p>