The vascular endothelium in parenchymal (intracerebral) arterioles is a critical mediator of normal cerebral function, serving as both a physical barrier and a modulator of blood flow within the brain. Ca2+ signaling and the Ca2+sensitive K+ channels, IK and SK, and TRPV4 in endothelial cells (ECs) activate pathways that transmit vasoregulatory signals to adjacent smooth muscle (SM) and along the endothelial lining of blood vessels. These signals may also communicate to nearby astrocytes and neurons to modulate neurovascular coupling (NVC). Despite the importance of parenchymal arteriolar (PA) endothelium, little is known about its control of vascular tone or potential influence on NVC in the brain.
Aim 1 will elucidate the properties and roles of endothelial Ca2+ signaling modalities and IK, SK and TRPV4 channels in PA ECs using a novel mouse model that expresses a Ca2+ biosensor (GCaMP2) in the endothelium. Exploiting these GCaMP2 mice, we have recently discovered a localized, stationary IPs-mediated Ca2+ signal in endothelial projections to the SM. This signal, termed a "pulsar", activates co-localized IK channels to modulate vascular tone.
Aim 2 will determine the impact of endothelial function on the SM of PAs, exploring Ca2+ signaling, membrane potential and vascular diameter.
Aim 3 builds on Aims 1 &2 to explore the role of the endothelium in the context of the brain, evaluating its effects on NVC and blood flow using a novel approach based on simultaneous measurement of astrocytic endfoot Ca2+ and vascular responses. The proposed project will provide signiflcant new insight into endothelial function and communication to SM in PAs. Close collaboration between Projects 1 and 2 will assure appropriate consideration of the physiological interactions and communication between endothelium and smooth muscle in PAs. In conjunction with Projects 3 and 4, Project 1 will help illuminate the role of the endothelium under the clinically important pathological conditions of ischemia/reperfusion injury and subarachnoid hemorrhage. This project should reveal novel targets involved in modulating blood flow in the brain and suggest therapeutic agents that do not require passage through the blood brain barrier.

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