Extracellular Matrix Glycoprotein Thrombospondin 1: An Overlooked Pathological Mediator in Vasculopathy of Systemic Sclerosis-Secondary Raynaud’s Phenomena

Abstract

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by a widespread vasculopathy, autoimmunity, and fibrosis of the skin and internal organs such as the lung and kidneys. Raynaud's phenomenon is the earliest recognized symptom of SSc. Unlike the primary Raynaud's disease, the condition responds well to management with non-pharmacological measures and pharmacological agents, Raynaud's phenomenon presented complex and progressive vasculopathy in the superficial vasculature embedded under the skin. The mechanisms underlying the development and progress of Raynaud's phenomenon are still unclear. Repeated Raynaud's phenomenon attacks are characteristic of ischemia-reperfusion episodes with different durations. What occurred to the superficial vascular bed highly possibly replicates at the vasculature in the vulnerable internal organ(s) at a later time and a distinctive pace. Elevated extracellular matrix glycoprotein thrombospondin 1 (TSP1) levels are found in circulation and throughout the skin in patients with SSc. TSP1-mediated vascular pathologies have been extensively investigated in multiple conditions, including hypertension, pulmonary arterial hypertension, and renal ischemia-reperfusion injury. TSP1 vasculopathy in these conditions is evidenced by a variety of function-modulating and vascular remodeling effects, specifically enhancing vasoconstrictive tone, platelet hyperaggregation, and inflammatory cell infiltration, inducing capillary rarefaction and promoting intimal thickening. In addition, the well-known anti-angiogenic property of TSP1 significantly impairs the self-repair and self-renewal capacity of growth factor-or stem cell-based regenerative therapies. Thanks to the growing knowledge of TSP1 vasculopathy in affected internal organs and adverse effects on regrowth, it is proposed that pathological levels of TSP1 may exert a similar pattern of multifaceted effects on the vasculature in SSc and regenerative therapies under investigation.