Neuronal activity triggers increases in blood flow in the central nervous system. This hemodynamic response, termed functional hyperemia, supplies active neurons with needed oxygen and nutrients and is essential for the health and proper function of the CNS. However, the neurovascular coupling mechanisms that mediate blood flow regulation remain controversial. A prominent hypothesis of neurovascular coupling holds that active neurons stimulate glial cells, evoking cytosolic Ca2+ increases and releasing vasodilating agents. However, this hypothesis has recently been challenged. Preliminary experiments from our laboratory offer a resolution to this controversy, suggesting that glial Ca2+ increases mediate capillary but not arteriole dilation. This hypothesis will be tested in the following aims.
Aim 1. Characterize Ca2+ signaling in Mller glial cell endfeet that terminate on capillaries and arterioles. We will test the hypothesis that flicker-evoked neuronal activity in the retina evokes rapid Ca2+ increases in the endfeet of Mller cells terminating on capillaries but not on arterioles.
Aim 2. Test the hypothesis that Mller cell Ca2+ signaling evokes capillary dilation. We will test this hypothesis by correlating changes in capillary diameter with spontaneous Ca2+ transients in Mller cell endfeet and with Ca2+ increases produced by intercellular Ca2+ waves in Mller cells.
Aim 3. Test the hypothesis that light-evoked capillary dilation is blocked in the absence of Mller cell Ca2+ signaling. We will test the hypothesis that capillary dilation is blocked in IP3R2 null mice, which lack glial cell Ca2+ signaling.
Aim 4. Determine the neurovascular coupling signaling pathways responsible for capillary dilation. We will test the hypothesis that neurovascular coupling onto capillaries is mediated by glial release of vasoactive arachidonic acid metabolites, including prostacyclin, prostaglandin E2, epoxyeicosatrienoic acids, and 20-hydroxy-eicosatetraenoic acid.
Project Relevance Active regulation of blood flow in the central nervous system supplies neurons with needed oxygen and nutrients and is essential for the health and proper function of the CNS. The proposed experiments will help determine the cellular and molecular mechanisms responsible for blood flow regulation and may lead to therapies for treating pathologies of the CNS vasculature, including Alzheimer?s disease, ischemic stroke, and hypertension in the brain and diabetic retinopathy, glaucoma, and age-related macular degeneration in the retina.
| Nippert, Amy R; Biesecker, Kyle R; Newman, Eric A (2018) Mechanisms Mediating Functional Hyperemia in the Brain. Neuroscientist 24:73-83 |
| Biesecker, Kyle R; Srienc, Anja I; Shimoda, Angela M et al. (2016) Glial Cell Calcium Signaling Mediates Capillary Regulation of Blood Flow in the Retina. J Neurosci 36:9435-45 |
