The human cutaneous circulation is an accessible, representative vascular bed for in vivo examination of mechanisms that contribute to vascular dysfunction with essential hypertension (HT). This proposal is a logical extension of our previous work investigating the vascular mechanisms underlying age and hypertensive-related changes in the control of reflex-mediated increases in skin blood flow. The proposed studies expand our previous research by pairing state-of-the-art nitric oxide (NO) specific in vivo methodologies (local heating and intradermal microdialysis) with in vitro analysis of human skin samples to examine the precise signaling mechanisms underlying impaired cutaneous vasodilatory (VD) signaling in humans with HT. Vascular dysfunction associated with HT is multifaceted but involves global decreases in NO bioavailability induced by impairments in constitutive NO-synthases (endothelial and neuronal NOS) expression and activity as well as increased oxidant stress. Although, cutaneous NO-dependent VD is clearly attenuated in hypertensive humans alterations in NO synthesis from the NOS isoforms producing NO are unresolved. Augmented inducible NOS and attenuated constitutive NOS isozymes are implicated in the inflammatory and hyperadrenergic neurovascular state associated with HT. Putative HT-induced mechanisms decreasing NO synthesis from the constitutive NOSs in the vasculature include (1) an inflammatory-induced increase in iNOS- synthesized NO which changes arginase enzyme kinetics (decreased Km) through S-nitrosylation, (2) a hemodynamic-induced upregulation of arginase-- both of which serve to limit NO synthesis through constitutive NOSs due to preferential metabolism if the NOS substrate L-arginine (L-arg) by arginase-- and (3) an increase in oxidant production through uncoupled NOS due to inadequate L-arg and/or essential cofactor (tetrahydriobiopterin (BH4)) availability. Upregulated arginase is also linked to the pathogenesis of hypertension-induced vessel wall remodeling through increased L-ornithine-mediated polyamine and proline synthesis. Thus, there is a mechanism linking inflammation, upregulated arginase, NOS uncoupling and deleterious vessel wall remodeling with HT. The proposed investigation will pair in vivo and in vitro methodologies to examine the putative link between inflammation, oxidant stress, and NO production in the cutaneous vasculature of humans with HT.
Specific Aim 1 will examine the NOS isoforms mediating attenuated cutaneous NO-dependent, Specific Aim 2 will examine the role of arginase in regulating L-arginine availability for NO synthesis through the constitutive NOSs, and Specific Aim 3 will examine roles of oxidative stress and cofactor BH4 availability as they relate to NOS uncoupling. We will also examine the mechanistic link between upregulated arginase and BH4 deficiency on NOS uncoupling by measuring real time relative oxidant production.

Public Health Relevance

One quarter of the population in the United States has undiagnosed or is being treated for essential hypertension. This health issue is pervasive and exacts emotional, physical, and financial costs. The results from these proposed studies will provide new and important information on the vascular effects of hypertension in the skin. Further, these results will provide insight into the regulation of skin blood flow and potential therapeutic intervention strategies for hypertensive vascular pathology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093238-05
Application #
8596842
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Reid, Diane M
Project Start
2009-07-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$320,785
Indirect Cost
$87,468
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
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Greaney, Jody L; Kutz, Jessica L; Shank, Sean W et al. (2017) Impaired Hydrogen Sulfide-Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults. Hypertension 69:902-909
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:
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Craighead, Daniel H; Alexander, Lacy M (2016) Topical menthol increases cutaneous blood flow. Microvasc Res 107:39-45
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Greaney, Jody L; Stanhewicz, Anna E; Proctor, David N et al. (2015) Impairments in central cardiovascular function contribute to attenuated reflex vasodilation in aged skin. J Appl Physiol (1985) 119:1411-20

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