A sustained increase in arterial blood pressure-i.e. hypertension-is a major cause of excess morbidity and mortality around the world. Chronic arterial pressure levels are thought to be established primarily by the kidney through regulation of total blood volume. The central hypothesis of this project is that veins contribute to long-term control of arterial pressure by actively redistributing blood from high compliance vascular compartments (peripheral, particularly splanchnic veins) to compartments of lower compliance (central veins, heart and arteries). Our goal is to show in intact conscious animals how neurohumoral mechanisms controlling the diameter of peripheral veins (peripheral vascular capacitance) affect arterial pressure and the development of hypertension. We will use two models of hypertension in rats: DOCA-salt;and a new model that we believe is based primarily on venoconstriction, i.e. S6c-induced hypertension. We will address our central hypothesis with the following Specific Aims. 1) Determine if venoconstriction causes body fluid volume redistribution during the development of hypertension by using three complementary methods to assess blood volume redistribution in conscious rats. 2) Establish that one mechanism of decreased vascular capacitance in hypertension is increased sympathetic nerve activity (and/or release of norepinephrine) in the splanchnic region using both direct nerve recording and regional norepinephrine spillover methods. 3) Show how sympathetic innervation to the splanchnic region affects regulation of vascular capacitance and arterial pressure by testing the effects on hypertension development of chronic splanchnic sympathetic denervation, and decreasing elevated superoxide levels in splanchic sympathetic ganglia using gene transfer methods. 4) Determine how venoconstriction ultimately leads to increased arterial pressure by testing the influence of small artery myogenic tone, large artery compliance, and cardiac sympathetic activity on the development of S6c-induced hypertension. Our ultimate objective is to identify novel strategies for treating human hypertension. Lay Summary: High blood pressure (hypertension) is a major human health problem. Many scientists feel the causes of hypertension can be found in abnormal function of the kidney or arteries. This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Michigan State University
East Lansing
United States
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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
Ayala-Lopez, Nadia; Watts, Stephanie W (2017) New actions of an old friend: perivascular adipose tissue's adrenergic mechanisms. Br J Pharmacol 174:3454-3465

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