A Mechanistic Approach to Understanding and Preventing the Vasculopathy of Raynaud’s Phenomenon

At comfortable temperatures, digital blood flow is already lower in individuals with Raynaud’s phenomenon (RP) compared to control subjects, and this falls to dramatically low levels during cold exposure. In control subjects, cooling selectively reduces blood flow through arteriovenous anastomoses (AVAs), whereas in RP both AVA and nutritional blood flow are decreased. Nutritional blood flow is somewhat challenged in primary RP (PRP) and severely restricted in the secondary RP of scleroderma (systemic sclerosis, SSc). Rather than representing responses to ischemia-reperfusion, the skin color changes that characterize PRP episodes likely reflect dynamic changes in blood flow through the different structural components of the cutaneous circulation. The reflex increase in sympathetic outflow in response to cold appears to be similar in control and RP subjects, whereas the resulting cutaneous vasoconstriction and the ability of local cooling to amplify the sympathetic response are increased in RP. The increased sympathetic activity can precipitate constriction of digital arteries in RP, and the constriction is dramatically increased by local cooling. In contrast, digital arteries of control subjects are minimally affected by these constrictor stimuli. Increased reactivity of RP vasculature appears to be mediated by increased activity of smooth muscle α2-ARs. The severe restriction in SSc nutritional blood flow likely reflects dysfunction in endothelium-dependent flow-mediated dilatation that is not present in PRP. Furthermore, in contrast to PRP, SSc is associated with a progressive systemic vasculopathy with structural deterioration and loss of the nutritional microvasculature. This SSc vasculopathy likely reflects a chronic state of destabilization that contributes to disruption of normal function and structure with impaired nutritional blood flow, microvascular rarefaction, impaired angiogenesis, vascular lesion development, and intravascular thrombosis. This vascular destabilization is responsible for some of the earliest features of SSc and likely contributes to progression of the disease including organ injury and fibrosis. Targeted therapy to restore protective signaling and vascular stability should be a highly effective approach to combat progression of the disease.