An Adrenergic System in Perivascular Adipose Tissue Regulates Vascular Tone

Michigan State University, East Lansing MI

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Abstract

? DESCRIPTION (provided by applicant): Perivascular adipose tissue (PVAT), fat that surrounds blood vessels, is active in its role of regulating vascular tone. PVAT has been discovered to be important to blood vessel function in many aspects: by altering the proliferation, migration, and inflammation of vascular smooth muscle in addition to modulating vascular tone by the release of vasoactive molecules. Our lab made the discovery that PVAT contains significant amounts of norepinephrine (NE), the main sympathetic vasoconstrictor. After the removal of splanchnic innervation by celiac ganglionectomy, mesenteric PVAT NE remained. We then found that NE in PVAT was releasable and caused vascular contraction. This strongly supports that the NE found in PVAT is releasable, affects vascular tone and at least in part is independent of the nerve. In piecing together this story we found positive stainin for NE synthesizing enzymes in PVAT by immunohistochemistry plus NE uptake transporter presence by RT-PCR, fluorescence staining and functional assays. This led us to hypothesize that PVAT synthesizes, metabolizes, and takes up NE to constitute an adrenergic system with established release. PVAT surrounds most blood vessels but we will be focusing on PVAT that surrounds the mesenteric arteries because: 1) the mesenteric resistance arteries hold over 30% of the body's blood volume, thus contraction in these arteries increases peripheral resistance and blood pressure, 2) an increased amount of viscerally located fat is associated with a higher risk of cardiovascular disease. In obesity, there is an increase in mesenteric PVAT mass and its normal anti-contractile properties are lost. We introduce an adrenergic system in mesenteric PVAT as the integral link that may connect obesity and hypertension. The aims for this research are: 1) To test the hypothesis that synthesis of NE occurs in PVAT. 2) To test the hypothesis that PVAT can take up NE through molecular transporters. 3) To test the hypothesis that metabolism of NE exists in PVAT and is important for NE inactivation. The aims will be tested using a combination of whole tissue and isolated cells with high-performance liquid chromatography, fluorescence confocal microscopy, Western blot, RT-PCR, and isometric contractility. These findings will advance the knowledge on PVAT's involvement in the control of blood pressure and provide valuable information into mechanisms behind the development of obesity-associated hypertension.