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Perivascular Adipose Tissue Controls Vasodilatation And Tissue Perfusion In Vivo Through Adipomuscular Microvascular Anastomoses
Alexander Turaihi, Carla Molthoff, Jasper Koning, Marie Jose Goumans, Connie Jimenez, John Yudkin, Yvo Smulders, Victor van Hinsbergh, Ed Eringa.
Amsterdam University Medical Centers, amsterdam, Netherlands.

Background: Vasodilation regulates delivery of substrates to tissues undergoing regeneration and growth. Perivascular adipose tissue (PVAT) controls vascular function through outside-to-inside communication and through vessel-to-vessel, or “vasocrine” signaling. We studied this hypothesis in mice by examining effects of surgical removal of local intramuscular PVAT on muscle blood flow (MBF) and glucose uptake. Methods: In lean C57/Bl6 mice we removed PVAT from the gracilis and femoral arteries. Mice underwent combined contrast-enhanced ultrasonography (CEUS) and Intravital Microscopy (IVM) to measure MBF and arteriolar diameter. PVAT vasodilator capacity was examined ex vivo using pressure myography. Local muscle glucose uptake was examined using positron emission tomography in vivo. Further, we used proteomic and microscopy experiments to understand the nature of the interaction between PVAT and the vessels. Results: Local PVAT removal reduces muscle glucose uptake by ±50 percent. Ex vivo, gracilis artery diameter increased in the presence of PVAT (26.2%±25%;p=0.03) but not in absence of PVAT. CEUS and IVM of gracilis artery showed that PVAT removal abolishes increases in arterial diameter (2.0%±7% vs. 14.5%±6%) and abrogated insulin-stimulated increase in muscle blood volume (microvascular recruitment or IMVR; -4.8%±7% vs. 35.7%±31%). The effect of PVAT on IMVR was mediated by distinct microvessels or anastomoses, which we showed using lightsheet microscopy of mice expressing mCherry in endothelial cells. Proteomics analysis revealed that PVAT removal significantly alters expression of 109 of 1719 detected proteins in muscle. Observed changes in protein expression included reduction of a mitochondrial protein cluster and of vesicle-associated membrane protein 5 (Vamp5), involved in Glut4 trafficking. Conclusion: We have found that PVAT within muscle regulates muscle perfusion, glucose uptake and muscle protein expression, communicating with the distal microcirculation via microvascular anastomoses. These data highlight the importance of PVAT in vascular and metabolic physiology, relevant for tissue regeneration and wound healing.

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