Cerebral blood flow is coupled to local neuronal demands. However, this coupling would be compromised without upstream dilation in pial arterioles to permit more blood to reach dilated downstream vessels. The process that permits vasodilating signals, originating in neurons, to reach the pial arterioles, which are isolated from parenchymal neurons by the glia limitans (GL), is unclear. The central hypothesis is that the signaling mechanisms involved will vary as the intensity of the neuronal activation increases. To that end, we will compare pial arteriolar responses during seizure (topical bicuculline) and sciatic nerve stimulation (SNS) in the presence of a variety of pharmacologic and molecular interventions. The following specific hypotheses will be tested: 1) Neuronal activation induces pial arteriolar dilation (PAD) via a signaling process involving astrocytes (and the GL) and vascular endothelium. These studies will use validated models for selective injury to the GL or endothelium. 2) Neuronal activation-induced PAD involves ATP efflux-related signal propagation within astrocytic networks and gap junctions and/or hemichannels. Both pharmacologic blockade and siRNA-linked knockdown will be used to target specific ATP receptors and connexin-43. 3) Paracrine factors arising from the GL act on pial vessels to elicit relaxation. The leading candidates are K+ AND breakdown products of ATP hydrolysis (adenosine;ADP), formed via ectonucleotidase (EN) action. The effects of specific pharmacologic blockers or siRNA-linked knockdown of K+ release channels (BKCa and Kir-4.1) and ENs, on seizure- vs SNS-induced PAD will be tested. 4) The released K+ and adenosine, respectively, stimulate Kir-2.1 channels and adenosine A2A receptors, perhaps interactively, on pial arteriolar smooth muscle. As above, specific pharmacologic and siRNA-based interventions will be applied. The results will provide vital new insights into how neurons, during periods of enhanced activity, signal specific cerebral vessels to dilate. The resulting increase in nutrient delivery to activated neurons acts to ensure normal brain function and provides protection in pathologic states. How vasodilating signals, originating in the neurons, reach the pial arterioles remain unclear. The core objective of this project is to identify mechanisms through which increased neuronal activity signals pial arterioles to dilate. The central hypothesis is that astrocytes and the glia limitans represent a vital signaling conduit in the pial arteriolar dilation arising from neural activation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088259-03
Application #
7842663
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Reid, Diane M
Project Start
2008-06-05
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2010
Total Cost
$387,500
Indirect Cost
Name
University of Illinois at Chicago
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Vetri, Francesco; Qi, Meirigeng; Xu, Haoliang et al. (2017) Impairment of neurovascular coupling in Type 1 Diabetes Mellitus in rats is prevented by pancreatic islet transplantation and reversed by a semi-selective PKC inhibitor. Brain Res 1655:48-54
Vetri, Francesco; Chavez, Rafael; Xu, Hao-Liang et al. (2013) Complex modulation of the expression of PKC isoforms in the rat brain during chronic type 1 diabetes mellitus. Brain Res 1490:202-9
Watcharotayangul, Jittiya; Mao, Lizhen; Xu, Haoliang et al. (2012) Post-ischemic vascular adhesion protein-1 inhibition provides neuroprotection in a rat temporary middle cerebral artery occlusion model. J Neurochem 123 Suppl 2:116-24
Vetri, Francesco; Xu, Haoliang; Paisansathan, Chanannait et al. (2012) Impairment of neurovascular coupling in type 1 diabetes mellitus in rats is linked to PKC modulation of BK(Ca) and Kir channels. Am J Physiol Heart Circ Physiol 302:H1274-84
Vetri, Francesco; Xu, Haoliang; Mao, Lizhen et al. (2011) ATP hydrolysis pathways and their contributions to pial arteriolar dilation in rats. Am J Physiol Heart Circ Physiol 301:H1369-77
Pelligrino, Dale A; Vetri, Francesco; Xu, Hao-Liang (2011) Purinergic mechanisms in gliovascular coupling. Semin Cell Dev Biol 22:229-36
Paulson, Olaf B; Hasselbalch, Steen G; Rostrup, Egill et al. (2010) Cerebral blood flow response to functional activation. J Cereb Blood Flow Metab 30:2-14
Pelligrino, Dale A; Xu, Hao-Liang; Vetri, Francesco (2010) Caffeine and the control of cerebral hemodynamics. J Alzheimers Dis 20 Suppl 1:S51-62
Paisansathan, Chanannait; Xu, Haoliang; Vetri, Francesco et al. (2010) Interactions between adenosine and K+ channel-related pathways in the coupling of somatosensory activation and pial arteriolar dilation. Am J Physiol Heart Circ Physiol 299:H2009-17
Shen, Bin; Vetri, Francesco; Mao, Lizhen et al. (2010) Aldose reductase inhibition ameliorates the detrimental effect of estrogen replacement therapy on neuropathology in diabetic rats subjected to transient forebrain ischemia. Brain Res 1342:118-26