Is scleroderma a vasculopathy?

Abstract

Described as an autoimmune collagen vascular disease, the most striking feature of scleroderma may be a systemic vasculopathy. This vasculopathy includes characteristic noninflammatory macrovascular and microvascular changes with dramatic and possibly occlusive formation of a thickened neointima. Scleroderma vessels also have an unusual endothelial phenotype, with loss of normal markers including vascular endothelial (VE)-cadherin. These endothelial cells express type 1 interferon and regulator of G protein signaling 5 (RGS5), two molecules associated with vascular rarefaction. These genes may be important because tissue is hypoxic with high levels of vascular endothelial growth factor (VEGF), especially early in the disease. The combination of VEGF and rarefaction is not necessarily paradoxical. VEGF-mediated angiogenesis creates labile vessels that may not survive unless the vessel acquires a smooth muscle coat. The combination of interferon and RGS5 is consistent with an antiangiogenic phenotype. We offer a hypothesis that places vascular injury at the center of this disease and also suggest possible clinical approaches for arresting and/or reversing the disease.

Figure 1

Endothelial phenotype in scleroderma compared with normal control. Immunohistochemistry for smooth muscle actin (SMA) stain (brown Dab stain) in the capillaries of scleroderma smooth muscle actin extends to the very top of the dermal papilla, unlike normal skin where SMA stain ends at the superficial horizontal plexus. SMA staining is also increased in the media of vessels in the reticular dermis (data not shown). SMA staining is present in scattered myofibroblasts present in the dermal collagen matrix of scleroderma. Regulator of G protein signaling 5 (RGS5) in situ expression of RNA is also increased in scleroderma. It is positive in cells (pink color) scattered in the dermal matrix, around blood vessels, and in the keratinocytes of the epidermis. Immunohistochemistry for the inflammatory marker CD123 (brown Dab stain) is increased in scleroderma tissue, especially around the blood vessels and in endothelial cells. In situ expression of interferon α (IFNA) RNA is increased dramatically in scleroderma skin (pink-colored cells) in a variety of cell types.