- Project 2 The splanchnic circulation is supplied by sympathetic nerves which control resistance and capacitance. Elevated sympathetic nerve activity (SNA) increases resistance and decreases capacitance causing increased blood pressure. Dysregulation of SNA and dilator mechanisms contribute to obesity-related hypertension. We will study how obesity disrupts molecular control of norepinephrine (NE) and ATP release at the arterial and venous sympathetic neuroeffector junction. A novel concept guiding these studies is that mesenteric perivascular fat (mPVAT) is a source of inflammatory mediators and norepinephrine (NE) that can alter sympathetic function.
Specific aim 1 : Prejunctional alpha2 adrenergic receptors (alpha2ARs) regulate NE and ATP release from sympathetic nerves and alpha2AR function is impaired in obesity-associated hypertension. The mechanisms responsible for impairment are linked to inflammation. We will test the hypothesis that alpha2AR function is impaired due to the action of mPVAT-derived inflammatory mediators.
Specific aim 2 : NE and ATP constrict and NE and endothelial derived nitric oxide (NO) relax vascular smooth muscle. Pannexin-1 is a smooth muscle ATP permeable channel and ATP contributes to arterial constriction caused by NE. This conclusion is based only on studies of exogenously applied NE; pannexin-1 contributions to neurogenic arterial or venous constriction have not been established. These studies will test the hypothesis that pannexin-1 contributes to neurogenic constriction in mesenteric arteries and veins and that pannexin-1 expression and function and NE and NO dilator mechanisms are impaired in obesity-associated hypertension.
Specific aim 3 :
This aim will focus on neurogenic constrictions and dilator mechanisms of human mesenteric arteries and veins obtained from obese patients undergoing gastric by-pass surgery and from non-obese patients undergoing intestinal or colonic resection. In addition to studies of basic mechanisms of sympathetic constriction of arteries and veins in the human splanchnic circulation, we will identify the mechanisms responsible for disruption of vascular tone and sympathetic neuroeffector transmission in obesity.

Public Health Relevance

? Project 2 Obesity related high blood pressure is a major public health issue that puts significant pressure on the health care system. The proposed studies will attempt to understand how obesity disrupts nervous system control of blood vessels. It is anticipated that the results will lead to drugs that could prevent or reverse obesity associated high blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL070687-15
Application #
9673180
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Maric-Bilkan, Christine
Project Start
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
15
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Michigan State University
Department
Type
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Diaz-Otero, Janice Marie; Yen, Ting-Chieh; Fisher, Courtney et al. (2018) Mineralocorticoid Receptor Antagonism Improves Parenchymal Arteriole Dilation Via a TRPV4-Dependent Mechanism and Prevents Cognitive Dysfunction in Hypertension. Am J Physiol Heart Circ Physiol :
Jackson, William F; Boerman, Erika M (2018) Voltage-gated Ca2+ channel activity modulates smooth muscle cell calcium waves in hamster cremaster arterioles. Am J Physiol Heart Circ Physiol 315:H871-H878
Ahmad, Maleeha F; Ferland, David; Ayala-Lopez, Nadia et al. (2018) Perivascular Adipocytes Store Norepinephrine by Vesicular Transport. Arterioscler Thromb Vasc Biol :ATVBAHA118311720
Matin, Nusrat; Fisher, Courtney; Jackson, William F et al. (2018) Carotid artery stenosis in hypertensive rats impairs dilatory pathways in parenchymal arterioles. Am J Physiol Heart Circ Physiol 314:H122-H130
Kumar, Ramya K; Darios, Emma S; Burnett, Robert et al. (2018) Fenfluramine-induced PVAT-dependent contraction depends on norepinephrine and not serotonin. Pharmacol Res :
Thelen, Kyan; Watts, Stephanie W; Contreras, G Andres (2018) Adipogenic potential of perivascular adipose tissue preadipocytes is improved by coculture with primary adipocytes. Cytotechnology 70:1435-1445
Restini, Carolina Baraldi A; Ismail, Alex; Kumar, Ramya K et al. (2018) Renal perivascular adipose tissue: Form and function. Vascul Pharmacol 106:37-45
Jackson, William F (2018) KV channels and the regulation of vascular smooth muscle tone. Microcirculation 25:
Fernandes, Roxanne; Garver, Hannah; Harkema, Jack R et al. (2018) Sex Differences in Renal Inflammation and Injury in High-Fat Diet-Fed Dahl Salt-Sensitive Rats. Hypertension 72:e43-e52
Diaz-Otero, Janice M; Fisher, Courtney; Downs, Kelsey et al. (2017) Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension. Hypertension 70:1113-1121

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