The main theme of this theme is that there is differential control of mesenteric arteries (MA) and veins (MV) by sympathetic nerves. We will identify these differences in detail and we will also identify the molecular mechanisms mediating deoxycorticosterone acetate (DOCA)-salt hypertension associated changes in sympathetic transmission to MA and MV in rats.
Specific aim 1 will test the hypothesis that sympathetic transmission to MA and MV is different and these mechanisms are differentially altered in hypertension. These studies will use intracellular electrophysiological techniques to record purinergic excitatory junction potentials (EJPs) caused by ATP released from sympathetic nerves supplying MA in vitro. We show that oxidative stress is responsible for impairment of purinergic signaling to MA in hypertension. We will also use continuous amperometry and fast scan cyclic voltametry (FSCV) to make electrochemical measurements of neurotransmitter release profiles from sympathetic nerves associated with MA and MV in vitro. Finally, these studies will use FSCV to study neurotransmitter release profiles from adrenal chromaffin cells in primary culture. The studies in this aim will show that sympathetic nerves supplying MA and MV use different neurotransmitters, release and clearance mechanisms and that sympathetic transmission to MA but not MV is altered in DOCA-salt hypertension. Adrenal chromaffin cells will used as a model of periarterial sympathetic nerves.
Specific aim 2 will test the hypothesis that B2-adrenergic receptor (AR)-mediated vasodilation is reduced in DOCA-salt rats. We propose that increased vascular tone in DOCA-salt hypertension is partly due to impairment of the link between the B2-AR-cAMP-protein kinase A signaling pathway and large conductance Ca[2+] activated K[+] (BK) channels in MA and MV. These studies will measure: B2-AR agonist-induced relaxations of MA and MV in vitro, BK channel currents using patch clamp methods and heterologous receptor and ion channel expression to study molecular mechanisms linking B2- ARs to BK channels.
Specific aim 3 will test the hypothesis that MV "reverse remodel" in DOCA-salt rats. Reverse remodeling is caused by activation of endothelin-B and a1-adrenergic receptor activation on venous smooth muscle cells which couple to activation of matrix metalloproteinase-2 and tenascin-C. Reverse remodeling is an adaptive response of veins to the decreased venous volume caused by volume shifts from the capacitance to the resistance side of the circulation in hypertension. These studies will provide new information about differential neurohumoral control of arteries and veins. We will also identify specific changes in neural control of arteries and veins in hypertension and this information will facilitate the development of new treatments for high blood pressure.

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
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Jackson, William F (2016) Boosting the signal: Endothelial inward rectifier K(+) channels. Microcirculation :
Matin, Nusrat; Fisher, Courtney; Jackson, William F et al. (2016) Bilateral common carotid artery stenosis in normotensive rats impairs endothelium-dependent dilation of parenchymal arterioles. Am J Physiol Heart Circ Physiol 310:H1321-9
Hammond, Bradley; Kreulen, David L (2016) Gene Therapy of the Peripheral Nervous System: Celiac Ganglia. Methods Mol Biol 1382:275-83
Ismail, Alex; Ayala-Lopez, Nadia; Ahmad, Maleeha et al. (2016) 3T3-L1 cells and perivascular adipocytes are not equivalent in amine transporter expression. FEBS Lett :
Seitz, Bridget M; Krieger-Burke, Teresa; Fink, Gregory D et al. (2016) Serial Measurements of Splanchnic Vein Diameters in Rats Using High-Frequency Ultrasound. Front Pharmacol 7:116
Matin, Nusrat; Pires, Paulo W; Garver, Hannah et al. (2016) DOCA-salt hypertension impairs artery function in rat middle cerebral artery and parenchymal arterioles. Microcirculation 23:571-579
Jackson, William F (2016) Arteriolar oxygen reactivity: where is the sensor and what is the mechanism of action? J Physiol 594:5055-77
Diaz-Otero, Janice M; Garver, Hannah; Fink, Gregory D et al. (2016) Aging is associated with changes to the biomechanical properties of the posterior cerebral artery and parenchymal arterioles. Am J Physiol Heart Circ Physiol 310:H365-75
Xu, Hui; Garver, Hannah; Fernandes, Roxanne et al. (2015) BK channel β1-subunit deficiency exacerbates vascular fibrosis and remodelling but does not promote hypertension in high-fat fed obesity in mice. J Hypertens 33:1611-23
Pires, Paulo W; Jackson, William F; Dorrance, Anne M (2015) Regulation of myogenic tone and structure of parenchymal arterioles by hypertension and the mineralocorticoid receptor. Am J Physiol Heart Circ Physiol 309:H127-36

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