Increased tyrosine phosphorylation mediates the cooling‐induced contraction and increased vascular reactivity of Raynaud's disease

Abstract

Objective. Increased levels of protein tyrosine kinase (PTK) are mechanistically associated with increased contractile responsiveness to cooling. This study tests the hypothesis that increased PTK activity mediates the increased vascular reactivity to agonists and cooling associated with primary Raynaud's disease (RD).Methods. The response of dermal arterioles isolated from control (n ‫؍‬ 29) and RD (n ‫؍‬ 29) subjects to contractile and dilatory agents at 37°C and 31°C was characterized using the microvessel perfusion technique. Fluorescence immunohistochemistry was used to measure tyrosine phosphorylation.Results. At 37°C, arteries from RD patients exhibited similar sensitivity to the specific ␣ 2 -adrenergic agonist UK 14,304, to serotonin, and to angiotensin II. At 31°C, however, the response to all 3 agonists was greater in the arterioles from the RD patients than in those from the control subjects. Agonist-induced contraction at both temperatures was reversed by cumulative addition of the PTK inhibitors genistein (1-30 M) and tyrphostin 47 (0.1-10 M). All arterioles from control subjects relaxed slightly in response to cooling, whereas more than half of those from RD patients contracted. This cooling-induced contraction was reversed by the cumulative addition of genistein. The 3 agonists elicited large increases in tyrosine phosphorylation only in arterial segments from RD patients at 31°C. Cooling from 37°C to 31°C elicited a large increase in tyrosine phosphorylation in arterioles from RD patients, but not those from control subjects. All increases in tyrosine phosphorylation could be prevented by genistein.Conclusion. Increased tyrosine phosphorylation mediates cooling-induced contraction and the increased vascular reactivity of skin arterioles from individuals with RD.

Impaired transient vasodilation and increased vasoconstriction to digital local cooling in primary Raynaud's phenomenon

“…This could support the involvement of the ROCK pathway in the pathophysiology of primary RP. Indeed, this would be consistent with previous findings that showed, in vitro, increased cooling-induced ␣ 2 -adrenergic constriction of arterioles isolated from patients with primary RP compared with controls, reversed by protein tyrosine kinase inhibitors (13). There is a similar tendency at 24°C, but it does not reach significance, probably because of a lack of power in our study.…”

“…Another mechanism could involve postjunctional ␣ 2C -adrenoreceptors, which are clustered distally, whereby increasing translocation of ␣ 2C -adrenoreceptors from cytosol to cell surface occurs during cooling, thus enhancing contraction (7). In vitro, Furspan et al (13) showed increased cooling-induced ␣ 2 -adrenergic constriction of arterioles isolated from patients with primary RP compared with controls, suppressed by protein tyrosine kinase inhibitors. The role of the RhoA/Rho kinase (ROCK) pathway in mediating vasoconstriction after local cooling in healthy subjects has been confirmed in vivo (31).…”

Syndrome De Raynaud Paraneoplasique : A Propos D’un Cas. Paraneoplastic Raynaud Syndroma: About One Case

“…Le phénomène de Raynaud est dit primitif si aucune pathologie sous-jacente n'est retrouvée et dans ce cas il est dit également maladie de Raynaud. L'existence d'antécédents familiaux est en faveur d'une atteinte primitive particulièrement chez les sujets jeunes [8]. Chez les femmes, la répartition entre maladie de Raynaud et syndrome de Raynaud secondaire est respectivement de 85% et 15 % alors que chez les hommes, elle est de 50 et 50%.…”

Chronic cerebral ischemia associated with Raynaud's syndrome

“…Диагностика СР достаточно стандартна, но при ассо-циации с ХИМ имеет некоторые особенности [22]. Она состоит из нескольких этапов и требует проведения до-полнительных лабораторных и инструментальных мето-дов обследования.…”