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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL070687-09
Application #
8374501
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
9
Fiscal Year
2012
Total Cost
$209,746
Indirect Cost
$65,475
Name
Michigan State University
Department
Type
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Jackson, W F (2017) Potassium Channels in Regulation of Vascular Smooth Muscle Contraction and Growth. Adv Pharmacol 78:89-144
Jackson, William F; Boerman, Erika M (2017) Regional heterogeneity in the mechanisms of myogenic tone in hamster arterioles. Am J Physiol Heart Circ Physiol 313:H667-H675
Fink, Gregory D; Phelps, Jeremiah T (2017) Can we predict the blood pressure response to renal denervation? Auton Neurosci 204:112-118
Fink, Gregory D (2017) Does Tail-Cuff Plethysmography Provide a Reliable Estimate of Central Blood Pressure in Mice? J Am Heart Assoc 6:
Ayala-Lopez, Nadia; Thompson, Janice M; Watts, Stephanie W (2017) Perivascular Adipose Tissue's Impact on Norepinephrine-Induced Contraction of Mesenteric Resistance Arteries. Front Physiol 8:37
Ismail, Alex; Ayala-Lopez, Nadia; Ahmad, Maleeha et al. (2017) 3T3-L1 cells and perivascular adipocytes are not equivalent in amine transporter expression. FEBS Lett 591:137-144
Tykocki, Nathan R; Boerman, Erika M; Jackson, William F (2017) Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles. Compr Physiol 7:485-581
Thelen, Kyan; Ayala-Lopez, Nadia; Watts, Stephanie W et al. (2017) Expansion and Adipogenesis Induction of Adipocyte Progenitors from Perivascular Adipose Tissue Isolated by Magnetic Activated Cell Sorting. J Vis Exp :
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
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

Showing the most recent 10 out of 97 publications