The cutaneous circulation is an accessible, representative vascular bed for in vivo examination of mechanisms that contribute to vascular dysfunction. This proposal is a logical extension of our previous work investigating the neurovascular mechanisms underlying age-related changes in the control of skin blood flow. The proposed studies expand our previous research to examine cutaneous vasodilatory (VD) signaling mechanisms in a hypercholesterolemic (HC) population. Impaired VD signaling with HC is characterized by an increase in oxidant stress coupled with the loss of endothelial nitric oxide (NO); together these events contribute to endothelial dysfunction associated with the pathogenesis of atherosclerosis. The precise mechanisms mediating decreased endothelial NO remain unclear. Putative sites through which NO may be decreased with HC include 1) oxidized low density lipoprotein (ox-LDL)-induced upregulation of vascular arginase activity, which preferentially metabolizes the common NO-synthase (NOS) substrate L- arginine (L-arg) to L-ornithine and urea and 2) endothelial (e)NOS uncoupling where eNOS contributes to increased oxidant stress by producing superoxide as a result of substrate (L-arg) or essential cofactor (tetrahydrobiopterin) deficiency. Additionally, there is a mechanistic link between ox-LDL-induced augmented vascular arginase activity and the pathogenesis of atherosclerosis through an increase in the polyamine and proline precursor L-ornithine which contributes to intimal thickening. To this end, the proposed investigations will systematically explore mechanisms affecting impaired NO- dependent cutaneous VD with HC using state-of-the-art in vivo skin specific techniques (local heating and intradermal microdialysis) paired with classic in vitro biochemical analysis of cutaneous biopsies.
Specific Aims 1 and 2 will mechanistically examine the roles of arginase, and oxidant stress in the context of eNOS uncoupling, respectively, to clarify their contributions to VD dysfunction with HC compared to an age- matched normocholesterolemic control group.
Specific Aim 3 will complement Aims 1 and 2 with in vitro biochemical analysis of eNOS and arginase gene expression, enzyme activity, and protein concentration.
Specific Aim 4 examines the mechanisms investigated in Aims 1-3 before and after a statin therapy intervention with atrovastatin. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089302-02
Application #
7494137
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Hasan, Ahmed AK
Project Start
2007-09-07
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$352,198
Indirect Cost
Name
Pennsylvania State University
Department
Miscellaneous
Type
Schools of Allied Health Profes
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Craighead, Daniel H; Smith, Caroline J; Alexander, Lacy M (2017) Blood pressure normalization via pharmacotherapy improves cutaneous microvascular function through NO-dependent and NO-independent mechanisms. Microcirculation 24:
Kenney, W Larry; Stanhewicz, Anna E; Bruning, Rebecca S et al. (2014) Blood pressure regulation III: what happens when one system must serve two masters: temperature and pressure regulation? Eur J Appl Physiol 114:467-79
Kenney, W Larry; Cannon, Joseph G; Alexander, Lacy M (2013) Cutaneous microvascular dysfunction correlates with serum LDL and sLOX-1 receptor concentrations. Microvasc Res 85:112-7
Alexander, Lacy M; Kutz, Jessica L; Kenney, W Larry (2013) Tetrahydrobiopterin increases NO-dependent vasodilation in hypercholesterolemic human skin through eNOS-coupling mechanisms. Am J Physiol Regul Integr Comp Physiol 304:R164-9
Holowatz, Lacy A; Kenney, W Larry (2011) Acute localized administration of tetrahydrobiopterin and chronic systemic atorvastatin treatment restore cutaneous microvascular function in hypercholesterolaemic humans. J Physiol 589:4787-97
Holowatz, Lacy A; Kenney, W Larry (2011) Oral atorvastatin therapy increases nitric oxide-dependent cutaneous vasodilation in humans by decreasing ascorbate-sensitive oxidants. Am J Physiol Regul Integr Comp Physiol 301:R763-8
Holowatz, Lacy A; Santhanam, Lakshmi; Webb, Alanah et al. (2011) Oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolaemic humans. J Physiol 589:2093-103
Simmons, Grant H; Wong, Brett J; Holowatz, Lacy A et al. (2011) Changes in the control of skin blood flow with exercise training: where do cutaneous vascular adaptations fit in? Exp Physiol 96:822-8