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New insights in the pathophysiology and molecular mechanisms implicated in cutaneous vasomotor response to cooling are emerging from recent literature. These advances are introducing significant changes in the management of Raynaud's phenomenon. In this review, we outline how these new findings are leading to novel methods of assessment and new opportunities for specific targeted therapy.New potential targets for treatment of Raynaud's phenomenon derive from experimental observations. Increased protein tyrosine kinase activity and tyrosine phosphorylation have been described in vascular smooth muscle cells in response to cooling and are linked to excessive α2-adrenergic response. Activation of Rho/Rho kinase pathway is triggered by increase of reactive oxygen species and up-regulates α2c-adrenergic receptors on the surface of vascular smooth muscle cells, thus determining an excessive vasoconstrictive response to cooling. This observation generated pilot trials testing rho-kinase inhibitors and α2c-adrenergic receptors antagonists in vasospastic conditions with encouraging results. Therapies already in use for pulmonary hypertension are also showing an effect in Raynaud's phenomenon. Studies evaluating anti-endothelin-1 (bosentan), phosphodiesterases inhibitors (sildenafil), and prostanoids (given for critical digital ischemia) in the treatment of Raynaud's phenomenon all determined improvement of symptoms and/or digital ischemic lesions. Novel techniques for better visualization and quantification of cutaneous microvascular defects are under development. The hope is that these new tools will allow earlier discrimination between primary and secondary Raynaud's phenomenon as well as a better way to predict outcome and response to therapy.Remarkable progress towards a rational approach to the management and treatment of Raynaud's phenomenon is emerging.