Aging and the control of human skin blood flow

Abstract

Human exposure to cold and heat stimulates cutaneous vasoconstriction and vasodilation via distinct sympathetic reflex and locally mediated pathways. The mechanisms mediating cutaneous vasoconstriction and vasodilation are impaired with primary aging, rendering the aged more vulnerable to hypothermia and cardiovascular complications from heat-related illness, respectively. This paper highlights recent findings discussing how age-related decrements in sympathetic neurotransmission contribute directly to thermoregulatory impairments, whereas changes in local intracellular signaling suggest a more generalized age-associated vascular dysfunction.

Figure 1

Schematic representation of sites of age-associated impairment in the sympathetic reflex thermoregulatory vasoconstriction response to cold. (A) Efferent skin sympathetic nerve activity (SSNA) is reduced, resulting in decreased perivascular nerve stimulation. (B) A decrease in axonal tetrahydrobiopterin (BH₄) bioavailability may contribute to the documented decrease in neuronal synthesis and release of norepinephrine (NE). (C) Reduced synthesis and/or release of neuropeptide Y (NPY) and potentially adenosine triphosphate (ATP) may contribute to the documented complete loss of sympathetic co-transmitter function. (D) The end-organ vasoconstrictor response mediated by post-junctional 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. Copyright permission obtained from Wolters Kluwer Health.

Figure 2

Schematic model of the role of Rho kinase in local cold-induced vasoconstriction. Localized cooling of cutaneous vessels and surrounding tissue stimulates the production of mitochondrial superoxide. Superoxide (O₂⁻) activates RhoA and Rho kinase, which can stimulate vasoconstriction through 2 distinct pathways: 1) Translocation of α_2C-adrenoceptors from intracellular storage to the cell membrane, joining α_2A- and α₁-adrenoceptors to bind norepinephrine (NE), which leads to increased intracellular [Ca²⁺] and Ca²⁺-dependent vasoconstriction through phosphorylation of myosin light chain (MLC) by myosin light chain kinase (MLCK); and 2) Inhibition of myosin light chain phosphatase (MLCP) permits extant MLC phosphorylation to remain, thereby stimulating constriction in the absence of an increase in intracellular [Ca²⁺]. --- = inhibitory effects; — = stimulatory/activation effects. Copyright permission obtained from Wolters Kluwer Health.

Figure 3

Pathway schematic of endothelial nitric oxide synthase (eNOS)-mediated vasodilation and RhoA/Rho kinase (ROCK)-mediated vasoconstriction in cutaneous vessels and the putative interactions between the two pathways. (A) eNOS-mediated vasodilation and ROCK-mediated vasoconstriction outlined as independent pathways. (B) The pro-dilator/anti-constrictor interactions of the two pathways that predominate in young, healthy skin under thermoneutral conditions. (C) The pro-constrictor/anti-dilator interactions of the two pathways that predominate during localized skin cooling and that are augmented in aged skin. --- = inhibitory effects; — = stimulatory effects. Copyright permission obtained from Wolters Kluwer Health.

Figure 4

During whole-body heating, cardiac output increases and blood flow to splanchnic and renal vascular beds decreases, redirecting flow to the cutaneous circulation. When healthy young men (left panel) were heated to the limit of their individual thermal tolerance using water-perfused suits, cardiac output essentially doubled and an additional liter of flow was redirected from visceral circulations, allowing skin blood flow to increase by 5.8 L/min. On average, healthy older men (right panel) responded with a much smaller increase in cardiac output coupled with a smaller decrease in flow from the combined visceral beds, providing only a 2.7 L/min increase in skin blood flow. These age differences in the integrated cardiovascular response to passive heating occurred despite similar increases in core temperature and decreases in central venous pressure.

Figure 5

Schematic representation of the putative mechanism of active vasodilation with relevant age-related alterations. The co-transmitter hypothesis, in which acetylcholine is co-released with an unknown neurotransmitter from sympathetic cholinergic nerves, is illustrated. Acetylcholine mediates the sweating response and may modulate the initial rise in active vasodilation through NO and COX-dependent prostanoid synthesis. In this schematic the unknown neurotransmitter and receptor (?) mediates vasodilation through adenylate cyclase mechanisms and may also increase NO synthesis through inositol triphosphate (IP₃)-mediated increases in intracellular calcium. Histamine also contributes to active vasodilation through NO-dependent and NO-independent mechanisms. Putative neurotransmitters involved in active vasodilation include vasoactive intestinal peptide (VIP), substance P, and calcitonin gene related peptide (CGRP) which may induce histamine release through the degranulation of cutaneous mast cells. With aging there is a reduction in both the functional neurotransmitter and NO contributions. NO-dependent vasodilation is decreased by an age-related upregulation of arginase activity and increased oxidant stress. Copyright permission obtained from Wolters Kluwer Health.

Figure 6

A schematic of the putative mechanisms affecting nitric oxide (NO) bioavailability in aged cutaneous vasculature. Primary human aging is associated with upregulated arginase activity which decreases L-arginine (L-arg) availability for NO synthesis through endothelial NO-synthase (eNOS). An age-associated increase in superoxide reacts with newly synthesized NO forming peroxynitrite (ONOO^•−), which oxidizes the critical eNOS cofactor tetrahydrobiopterin (BH4). Decreased substrate (L-arg) and/or cofactor (BH₄) availability leads to eNOS uncoupling where eNOS produces superoxide (O^•−) instead of NO. Copyright permission obtained from Wolters Kluwer Health.

Figure 7

Individual and mean subject responses at baseline and at the plateau in cutaneous vascular conductance (%CVCmax) as a percentage of maximum. Data from the age matched control subjects are displayed in the left hand panels and the chronic low-dose aspirin subjects are displayed in the right hand panels. Subjects taking chronic low-dose aspirin therapy displayed a significantly attenuated increase in skin blood flow during hyperthermia in both A. the control sites and B. the NO-synthase inhibited (L-NAME treated) sites. Copyright permission obtained from The American Physiological Society.

Figure 8

Schematic representation of the putative mechanism of local heating-induced vasodilation with relevant age-related alterations. The initial vasodilation in response to local heating is mediated by a sensory axon reflex. Activation of valliniod type 1 receptors (VR1) has been implicated in the sensory nerve stimulation of the axon reflex. Putative neurtotransmitters (?) mediating the axon reflex include substance P and calcitonin gene related peptide (CGRP). The secondary (neurally independent) phase of local heating is predominantly (~70%) dependent on NO. Temperature-induced endothelial NOS (eNOS) activation and increased heat shock protein 90 have been implicated in the plateau phase. Aging-related alterations in the mechanism include a decreased axon reflex with a reduction in the capsaicin-sensitive primary afferent contribution. The NO-dependent plateau is also significantly reduced in aged skin. Copyright permission obtained from Wolters Kluwer Health.