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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Reid, Diane M
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Pennsylvania State University
Schools of Allied Health Profes
University Park
United States
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Greaney, Jody L; Kenney, W Larry; Alexander, Lacy M (2016) Sympathetic regulation during thermal stress in human aging and disease. Auton Neurosci 196:81-90
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
Greaney, Jody L; Alexander, Lacy M; Kenney, W Larry (2015) Sympathetic control of reflex cutaneous vasoconstriction in human aging. J Appl Physiol (1985) 119:771-82
Greaney, Jody L; Stanhewicz, Anna E; Kenney, W Larry et al. (2015) Impaired increases in skin sympathetic nerve activity contribute to age-related decrements in reflex cutaneous vasoconstriction. J Physiol 593:2199-211
Bruning, R S; Kenney, W L; Alexander, L M (2015) Altered skin flowmotion in hypertensive humans. Microvasc Res 97:81-7
Kutz, Jessica L; Greaney, Jody L; Santhanam, Lakshmi et al. (2015) Evidence for a functional vasodilatatory role for hydrogen sulphide in the human cutaneous microvasculature. J Physiol 593:2121-9
Stanhewicz, Anna E; Greaney, Jody L; Kenney, W Larry et al. (2014) Sex- and limb-specific differences in the nitric oxide-dependent cutaneous vasodilation in response to local heating. Am J Physiol Regul Integr Comp Physiol 307:R914-9
Greaney, Jody L; Stanhewicz, Anna E; Kenney, W Larry et al. (2014) Lack of limb or sex differences in the cutaneous vascular responses to exogenous norepinephrine. J Appl Physiol (1985) 117:1417-23
Greaney, Jody L; Stanhewicz, Anna E; Kenney, W Larry et al. (2014) Muscle sympathetic nerve activity during cold stress and isometric exercise in healthy older adults. J Appl Physiol (1985) 117:648-57
Smith, Caroline J; Santhanam, Lakshmi; Alexander, Lacy M (2013) Rho-Kinase activity and cutaneous vasoconstriction is upregulated in essential hypertensive humans. Microvasc Res 87:58-64

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