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Thompson-Torgerson CS, Holowatz LA, Flavahan NA, Kenney WL. Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin. Am J Physiol Heart Circ Physiol 292: H1700-H1705, 2007. First published December 15, 2006; doi:10.1152/ajpheart.01078.2006 is the initial thermoregulatory response to cold exposure and can be elicited through either whole body or localized skin cooling. However, the mechanisms governing local cold-induced VC are not well understood. We tested the hypothesis that Rho kinase participates in local cold-induced cutaneous VC. In seven men and women (20 -27 yr of age), up to four ventral forearm skin sites were instrumented with intradermal microdialysis fibers for localized drug delivery during cooling. Skin blood flow was monitored at each site with laserDoppler flowmetry while local skin temperature was decreased and maintained at 24°C for 40 min. Cutaneous vascular conductance (CVC; laser-Doppler flowmetry/mean arterial pressure) was expressed as percent change from 34°C baseline. During the first 5 min of cooling, CVC decreased at control sites (lactated Ringer solution) to Ϫ45 Ϯ 6% (P Ͻ 0.001), increased at adrenoceptor-antagonized sites (yohimbine ϩ propranolol) to 15 Ϯ 14% (P ϭ 0.002), and remained unchanged at both Rho kinase-inhibited (fasudil) and adrenoceptor-antagonized ϩ Rho kinase-inhibited sites (yohimbine ϩ propranolol ϩ fasudil) (Ϫ9 Ϯ 1%, P ϭ 0.4 and Ϫ6 Ϯ 2%, P ϭ 0.4, respectively). During the last 5 min of cooling, CVC further decreased at all sites when compared with baseline values (control, Ϫ77 Ϯ 4%, P Ͻ 0.001; adrenoceptor antagonized, Ϫ61 Ϯ 3%, P Ͻ 0.001; Rho kinase inhibited, Ϫ34 Ϯ 7%, P Ͻ 0.001; and adrenoceptor antagonized ϩ Rho kinase inhibited sites, Ϫ35 Ϯ 3%, P Ͻ 0.001). Rho kinase-inhibited and combined treatment sites were significantly attenuated when compared with both adrenoceptor-antagonized (P Ͻ 0.01) and control sites (P Ͻ 0.0001). Rho kinase mediates both earlyand late-phase cold-induced VC, supporting in vitro findings and providing a putative mechanism through which both adrenergic and nonadrenergic cold-induced VC occurs in an in vivo human thermoregulatory model. fasudil; local cooling; vascular function; adrenergic; norepinephrine CUTANEOUS VASOCONSTRICTION (VC) is the initial thermoregulatory response to defend against cold exposure, effectively minimizing heat loss to the environment. Whole body skin cooling evokes reflex VC, which involves the release of norepinephrine and sympathetic cotransmitters from sympathetic adrenergic axon terminals (38 -40, 42), whereas localized cooling of the cutaneous blood vessels and surrounding tissue engages local (i.e., nonreflex) VC mechanisms that are mediated, in part, by ␣ 2 -adrenoceptors (12,14,27,34). Reflex and local VC are not mutually exclusive responses and often operate in concert during cold exposure to maximize VC (1). However, whereas reflex VC mechanisms are relatively well understood, the mechanisms that govern local cold-induced VC have not been fully elucidated.Localized ...

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.

Raynaud's phenomenon, which is characterized by intense cold-induced constriction of cutaneous arteries, is more common in women compared with men. Cold-induced constriction is mediated in part by enhanced activity of alpha(2C)-adrenoceptors (alpha(2C)-ARs) located on vascular smooth muscle cells (VSMs). Experiments were therefore performed to determine whether 17beta-estradiol regulates alpha(2C)-AR expression and function in cutaneous VSMs. 17beta-Estradiol (0.01-10 nmol/l) increased expression of the alpha(2C)-AR protein and the activity of the alpha(2C)-AR gene promoter in human cultured dermal VSMs, which was assessed following transient transfection of the cells with a promoter-reporter construct. The effect of 17beta-estradiol was associated with increased accumulation of cAMP and activation of the cAMP-responsive Rap2 GTP-binding protein. Transient transfection of VSMs with a dominant-negative mutant of Rap2 inhibited the 17beta-estradiol-induced activation of the alpha(2C)-AR gene promoter, whereas a constitutively active mutant of Rap2 increased alpha(2C)-AR promoter activity. The effects of 17beta-estradiol were inhibited by the estrogen receptor (ER) antagonist, ICI-182780 (1 micromol/l), and were mimicked by a cell-impermeable form of the hormone (estrogen:BSA) or by the selective ER-alpha receptor agonist 4,4',4'''-(4-propyl-[(1)H]-pyrazole-1,3,5-triyl)tris-phenol (PPT; 10 nmol/l) or the selective ER-beta receptor agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; 10 nmol/l). Therefore, 17beta-estradiol increased expression of alpha(2C)-ARs by interacting with cell surface receptors to cause a cAMP/Rap2-dependent increase in alpha(2C)-AR transcription. In mouse tail arteries, 17beta-estradiol (10 nmol/l) increased alpha(2C)-AR expression and selectively increased the cold-induced amplification of alpha(2)-AR constriction, which is mediated by alpha(2C)-ARs. An estrogen-dependent increase in expression of cold-sensitive alpha(2C)-ARs may contribute to the increased activity of cold-induced vasoconstriction under estrogen-replete conditions.