The overall goal of this project is to investigate the underlying mechanisms by which different durations of ischemia and reperfusion (l/R) alter endothelium-dependent vasodilation and vascular tone in middle cerebral arteries (MCA) and parenchymal arterioles (PA) in ways that may affect postischemic reperfusion and stroke outcome. Our preliminary and published studies demonstrate a specific effect of reperfusion on the function of MCA vs. PA. While longer reperfusion durations impair basal tone and myogenic reactivity in MCA, basal tone is considerably greater and well-preserved in PA regardless of l/R. We have hypothesized that the greater basal tone of PA during postichemic reperfusion could contribute to infarct expansion and worsen stroke outcome by limiting reperfusion CBF. In addition, there is an enhanced influence of EDHF on resting tone in PA at short reperfusion durations (30 minutes), but a significantly diminished influence after longer reperfusion (2 hours). The contribution of these vasodilator mechanisms to stroke outcome after different durations of reperfusion will also be investigated. The studies outlined in this project will investigate the effect of l/R on small- and intermediate-conductance calcium-activated potassium channels (SK, IK) in endothelium, and transient receptor potential (TRP) channels and voltage-dependent calcium channels (Cav) in vascular smooth muscle. These channels are important for the control of membrane potential and cell calcium that define vascular function and are a major focus of this Program Project Grant. In addition, we will investigate how peroxynitrite, a reactive nitrogen species produced during postischemic reperfusion, affects smooth muscle membrane potential and cell calcium to cause vasoconstriction, in PA and if treatment to decrease peroxynitrite levels improves stroke outcome and vascular function. The proposed experiments will be in close collaboration with the investigators and Cores of this Program Project Grant. Project 1 investigates calcium signaling in endothelium of PA also with a focus on SK/IK channels under normal conditions and their role in controlling cerebral blood flow. Project 2 is focused on myogenic activity in PA and the role of Cav and TRP channels in mediating this response, a similar focus as in this Project under conditions of l/R. Project 4 will investigate similar changes under conditions of hemorrhagic stroke that could provide valuable insight into both these conditions. We will use a powerful combination of state-of-the-art techniques to study changes in cell calcium, ion channel function, and membrane potential in MCA and PA after focal cerebral ischemia. The considerable expertise of our group of investigators in ion channel function and cell calcium will be utilized fully to provide technical and conceptual support for our Project.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Vermont & St Agric College
United States
Zip Code
Wallace, Kedra; Tremble, Sarah M; Owens, Michelle Y et al. (2015) Plasma from patients with HELLP syndrome increases blood-brain barrier permeability. Reprod Sci 22:278-84
Cipolla, Marilyn J; Sweet, Julie; Chan, Siu-Lung et al. (2014) Increased pressure-induced tone in rat parenchymal arterioles vs. middle cerebral arteries: role of ion channels and calcium sensitivity. J Appl Physiol (1985) 117:53-9
Longden, Thomas A; Dabertrand, Fabrice; Hill-Eubanks, David C et al. (2014) Stress-induced glucocorticoid signaling remodels neurovascular coupling through impairment of cerebrovascular inwardly rectifying K+ channel function. Proc Natl Acad Sci U S A 111:7462-7
Dunn, Kathryn M; Nelson, Mark T (2014) Neurovascular signaling in the brain and the pathological consequences of hypertension. Am J Physiol Heart Circ Physiol 306:H1-14
Cipolla, Marilyn J; Chan, Siu-Lung; Sweet, Julie et al. (2014) Postischemic reperfusion causes smooth muscle calcium sensitization and vasoconstriction of parenchymal arterioles. Stroke 45:2425-30
Mingin, Gerald C; Peterson, Abbey; Erickson, Cuixia Shi et al. (2014) Social stress induces changes in urinary bladder function, bladder NGF content, and generalized bladder inflammation in mice. Am J Physiol Regul Integr Comp Physiol 307:R893-900
Schreurs, Malou P H; Cipolla, Marilyn J (2014) Cerebrovascular dysfunction and blood-brain barrier permeability induced by oxidized LDL are prevented by apocynin and magnesium sulfate in female rats. J Cardiovasc Pharmacol 63:33-9
Krishnamoorthy, Gayathri; Sonkusare, Swapnil K; Heppner, Thomas J et al. (2014) Opposing roles of smooth muscle BK channels and ryanodine receptors in the regulation of nerve-evoked constriction of mesenteric resistance arteries. Am J Physiol Heart Circ Physiol 306:H981-8
Mercado, Jose; Baylie, Rachael; Navedo, Manuel F et al. (2014) Local control of TRPV4 channels by AKAP150-targeted PKC in arterial smooth muscle. J Gen Physiol 143:559-75
Hill-Eubanks, David C; Gonzales, Albert L; Sonkusare, Swapnil K et al. (2014) Vascular TRP channels: performing under pressure and going with the flow. Physiology (Bethesda) 29:343-60

Showing the most recent 10 out of 42 publications