: This research program is an extension of a project regarding the role of NO in the control of cerebral vasodilation at the arteriolar level. The studies in this competing renewal application will address control mechanisms occurring chiefly in cerebral vascular smooth muscle (VSM) at the level of cyclic GMP and cyclic AMP. A basic premise of the project is that the cyclic nucleotide pathways do not function as separate entities, but rather interact through a process generically labeled as """"""""crosstalk."""""""" The central hypothesis of this proposal is that, through crosstalk regulation in VSM, each cyclic nucleotide is capable of regulating the vasodilating actions of its counterpart via interactions with phosphodiesterases (PDEs). The project will address two basic hypotheses. First, crosstalk control by one cyclic nucleotide, at the PDE level, occurs by reducing the hydrolysis of its counterpart. Second, the reduction in hydrolytic function may occur by a direct action of the cyclic nucleotide or its kinase on the PDE itself or via promoting a kinase-related subcellular sequestration of the PDE away from the bulk pool of cyclic nucleotides residing in the cytosol.
Three specific aims will be addressed, based upon the 3 principal PDEs found in cerebral VSM-the cAMP-""""""""preferring"""""""" PDE3, the cAMP-specific PDE4, and the cGMP-specific PDE5. Primary increases in endogenous cAMP and cGMP production will be elicited by the adenylyl and guanylyl cyclase activators, forskolin and YC-1, respectively. Two experimental models will used in these studies: the established closed cranial window, intravital microscopy system designed for monitoring pial arteriolar diameter changes in anesthetized rats and primary cultures of rat pial vascular smooth muscle. Both models will be used to test the first hypothesis. Those studies will involve the use of carefully chosen selective enzyme inhibitors and activators. In most cases, those selectivities have been validated by us. In addition, confirmation of the ability of one cyclic nucleotide to influence the content of the other, in the presence of these pharmacologic manipulations, will be obtained using the culture system. Sequestration issues will be addressed using pial VSM cells and high-resolution immunofluoresence detection techniques. Those studies will generally involve assessments of the relative intra-nuclear vs cytosolic expression of the 3 PDEs, in the absence and the presence of increases in the levels of the counterpart cyclic nucleotide. The roles of the cyclic nucleotide kinases will also be addressed in this regard. These studies will provide important new information regarding the mechanisms controlling a physiologic process vital to normal brain function and survival-cerebral arteriolar dilation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052594-07
Application #
6752433
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Goldman, Stephen
Project Start
1997-04-01
Project End
2005-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
7
Fiscal Year
2004
Total Cost
$311,740
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
Xu, Hao-Liang; Vetri, Francesco; Lee, Hae-Kyung et al. (2009) Estrogen replacement therapy in diabetic ovariectomized female rats potentiates postischemic leukocyte adhesion in cerebral venules via a RAGE-related process. Am J Physiol Heart Circ Physiol 297:H2059-67
Xu, Hao-Liang; Salter-Cid, Luisa; Linnik, Matthew D et al. (2006) Vascular adhesion protein-1 plays an important role in postischemic inflammation and neuropathology in diabetic, estrogen-treated ovariectomized female rats subjected to transient forebrain ischemia. J Pharmacol Exp Ther 317:19-29
Krause, Diana N; Duckles, Sue P; Pelligrino, Dale A (2006) Influence of sex steroid hormones on cerebrovascular function. J Appl Physiol 101:1252-61
Xu, Hao-Liang; Ye, Shuhua; Baughman, Verna L et al. (2005) The role of the glia limitans in ADP-induced pial arteriolar relaxation in intact and ovariectomized female rats. Am J Physiol Heart Circ Physiol 288:H382-8
Xu, Hao-Liang; Wolde, Hailemariam M; Gavrilyuk, Vitaliy et al. (2004) cAMP modulates cGMP-mediated cerebral arteriolar relaxation in vivo. Am J Physiol Heart Circ Physiol 287:H2501-9
Xu, Hao-Liang; Baughman, Verna L; Pelligrino, Dale A (2004) Estrogen replacement treatment in diabetic ovariectomized female rats potentiates postischemic leukocyte adhesion in cerebral venules. Stroke 35:1974-8
Xu, Hao-Liang; Gavrilyuk, Vitaliy; Wolde, Hailemariam M et al. (2004) Regulation of rat pial arteriolar smooth muscle relaxation in vivo through multidrug resistance protein 5-mediated cGMP efflux. Am J Physiol Heart Circ Physiol 286:H2020-7
Xu, H L; Koenig, H M; Ye, S et al. (2004) Influence of the glia limitans on pial arteriolar relaxation in the rat. Am J Physiol Heart Circ Physiol 287:H331-9
Xu, H L; Santizo, R A; Baughman, V L et al. (2003) Nascent EDHF-mediated cerebral vasodilation in ovariectomized rats is not induced by eNOS dysfunction. Am J Physiol Heart Circ Physiol 285:H2045-53
Xu, H-L; Feinstein, D L; Santizo, R A et al. (2002) Agonist-specific differences in mechanisms mediating eNOS-dependent pial arteriolar dilation in rats. Am J Physiol Heart Circ Physiol 282:H237-43

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