Peripheral mechanisms of thermoregulatory control of skin blood flow in aged humans

Abstract

Human skin blood flow is controlled via dual innervation from the sympathetic nervous system. Reflex cutaneous vasoconstriction and vasodilation are both impaired with primary aging, rendering the aged more vulnerable to hypothermia and cardiovascular complications from heat-related illness. Age-related alterations in the thermoregulatory control of skin blood flow occur at multiple points along the efferent arm of the reflex, including 1) diminished sympathetic outflow, 2) altered presynaptic neurotransmitter synthesis, 3) reduced vascular responsiveness, and 4) impairments in downstream (endothelial and vascular smooth muscle) second-messenger signaling. This mechanistic review highlights some of the recent findings in the area of aging and the thermoregulatory control of skin blood flow.

Fig. 1.

Normalized cutaneous vascular conductance to a percentage of baseline for reflex vasoconstriction study and a percentage of maximum for reflex vasodilation studies in both young (18–30 yr) and older (65–85 yr) humans. Reflex vasoconstriction and vasodilation are significantly attenuated in aged skin. ΔT_or, change in oral temperature; T̄_sk, mean skin temperature.

Fig. 2.

A schematic depiction of the neurovascular mechanisms mediating reflex cutaneous vasoconstriction with relevant age-related changes. Efferent sympathetic nerve activity (SSNA) is reduced, resulting in decreased perivascular nerve stimulation. A decrease in axonal tetrahydrobiopterin (BH₄) and tyrosine bioavailability contributes to the documented decrease in neuronal synthesis and release of norepinephrine (NE). Reduced synthesis and/or release of neuropeptide Y (NPY) and potentially adenosine triphosphate (ATP) may contribute to the documented complete loss of sympathetic cotransmitter function. The end-organ vasoconstrictor response mediated by postjunctional α-adrenergic, Y₁, and P_2x receptors (for NE, NPY, and ATP, respectively) is reduced, although it is unclear whether this loss of sensitivity is due to changes in receptor population, intracellular second-messenger signaling pathways, or a combination of the two. Finally, there are alterations in vascular smooth muscle second-messenger signaling, including an increased reliance on Rho-kinase-dependent mechanisms in aged skin. See text for details. H₂O₂, hydrogen peroxide; ONOO⁻, peroxynitrite; O₂⁻, superoxide; BH₂, dihydrobiopterin; DA, dopamine; TH, tyrosine hydroxylase; αARs, adrenoreceptors; Y₁, NPY receptor; P_2X, puridine receptor; DAG, diacylglycerol; IP₃, inositol triphosphate; CaM, calmodulin; ROCK, Rho-kinase; P, phosphate; GTP, guanosine triphosphate; GDP, guanosine diphosphate; VC, vasoconstriction; VD, vasodilation; l-DOPA, l-3,4-dihydroxyphenylalanine; GEF, guanine nucleotide exchange factor; GAPs, GTPase-activating proteins; MLC, myosin light chain.

Fig. 3.

A schematic representation of the putative mechanisms of active vasodilation with relevant age-related alterations. The cotransmitter(s) hypothesis, in which acetylcholine is co-released with an unknown neurotransmitter(s) from sympathetic cholinergic nerves, is illustrated. In this schematic, the unknown neurotransmitter(s) and receptor(s) (?) mediates vasodilation through adenylate cyclase (AC) mechanisms and may also increase nitric oxide (NO) synthesis through IP₃-mediated increases in intracellular calcium. Putative cotransmitters involved in active vasodilation include vasoactive intestinal peptide (VIP), substance P (Sub P), and calcitonin gene-related peptide (CGRP). With aging, there is a reduction in the functional cotransmitter(s), NO, and cyclooxygenase (COX)-derived vasodilator contributions. NO-dependent vasodilation is decreased by an age-related upregulation of arginase activity and increase oxidant stress. A novel role for platelets is also depicted. See text for details. VIP, vasoactive intestinal peptide; ACh, acetycholine; H₁, histamine 1 receptor; NK₁, neurokinin 1 receptor; VPAC, vasoactive intestinal peptide receptor; P₂Y, puridine receptor; M₃, muscarinic receptor; NOS, NO synthase; PGI₂, prostaglandin I₂; l-arg, l-arginine; l-orn, l-ornithine; VSM, vascular smooth muscle; PLA₂, phospholipase A₂; AA, arachadonic acid; TXA₂, thromboxane synthase; TP, thromboxane prostaniod receptor; DAG, diacylglycerol; P, phosphate; cAMP, cyclic adenosine monophosphate; sGC, soluble guanalate cyclase; cGMP, cyclic guanosine monophosphate.