Hypertension is a significant public health concern around the world because it is an important risk factor for cardiovascular and renal disease. Most efforts to understand and treat this condition have focused logically on either the kidney or arteries. The three central and complementary themes of this Program Project are: veins play an important role in the long-term control of arterial pressure;neurohumoral mechanisms regulating venous smooth muscle activity are fundamentally different from those of arteries;and abnormalities in neurohumoral regulation specific to veins are a significant part of the etiology of hypertension. The overall strategy for achieving the experimental goals listed above will be to capitalize on the diverse scientific expertise of individual project investigators - from whole animal studies to molecular approaches - to test in detail a single integrated hypothesis linking the sympathetic nervous system, ET-1 and reactive oxygen species to the control of venomotor tone and blood pressure. We will focus our efforts on understanding the etiology of hypertension primarily using the DOCA-salt model of hypertension in rats. Project 1 will assess venous function in conscious rats using a number of whole body measures including blood pressure, mean circulatory filling pressure, cardiac output, and fluid volume distribution using bioimpedance. Project 2 focuses on differences in adrenergic neurotransmission in veins versus arteries and the adaptive mechanisms of veins to hypertension. Project 3 aims at comparing properties of sympathetic neurons targeting arteries, veins and the heart in normotensive and hypertensive rats, and the generation and effects of superoxide and other reactive oxygen species in sympathetic ganglia. Project 4 will investigate arterial vs venous function by examining how ET receptors operate differently in arteries versus veins, why arteries and veins have different reactive oxygen species metabolizing systems and why veins and arteries have a different response (adaptive or otherwise) to the stresses of 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 #
8114095
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Maric-Bilkan, Christine
Project Start
2002-07-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
9
Fiscal Year
2012
Total Cost
$1,409,949
Indirect Cost
$471,360
Name
Michigan State University
Department
Pharmacology
Type
Schools of Medicine
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
Jackson, W F (2017) Potassium Channels in Regulation of Vascular Smooth Muscle Contraction and Growth. Adv Pharmacol 78:89-144

Showing the most recent 10 out of 106 publications