Vascular damage and lack of angiogenesis in systemic sclerosis skin

Abstract

The aim of this study was to analyse microvascular damage and compensatory angiogenesis in skin from patients with systemic sclerosis (SSc) compared with systemic lupus erythematosus (SLE), Raynaud's phenomenon (RP) and healthy controls. Immunohistochemistry was used for skin biopsies (9 SSc, 10 SLE, 9 RP and 12 healthy controls) using von Willebrand factor and beta3 integrin subunit specific antibodies, TechMate immunostaining robot and biotin-streptavidin protocol. In the early stages of SSc, vWF was found in the perivascular space and interstitial matrix in papillary but not in the reticular dermis, in particular around small oedematous blood vessels infiltrated by mononuclear cells. The extravascular release of vWF in SSc specimens was associated with weak or even a total lack of immunoreactivity within the associated endothelial cells. Late stages of SSc were characterised by loss of the dermal papillae, subepidermal fibrosis, hypovascularity and strong endothelial vWF expression without extravascular leakage. In all SSc patients studied only a few vascular profiles were weakly immunostained for beta3 integrin subunit. This work demonstrates that vWF is not only released into the systemic circulation, but is also leaked to the perivascular space/matrix. This local release and deposition of vWF is probably a sensitive and early marker of microvascular involvement in SSc pathogenesis. Local vWF release may play a role in platelet adhesion, aggregation, thrombogenesis and dermal connective tissue remodelling. In spite of some attempts towards compensatory angiogenesis in SSc, as evidenced by beta3 integrin subunit expression, it was evident that the angiogenic response was not able to prevent the development of hypovascularity during the advanced stages of the disease.

Effects of prostaglandin E1α cyclodestrin treatment on endothelial dysfunction in patients with systemic sclerosis

“…Systemic sclerosis (SSc) is characterized by a variety of structural and functional abnormalities of the large and small vessels, which accounts for the evidence that this condition is accompanied by an increased incidence of cardiovascular disease compared with the general population [1][2][3][4][5]. One of these abnormalities is an imbalance between the endothelial secretion of nitric oxide (NO) and endothelin I, which means that the SSc-related alterations include endothelial dysfunction [6,7], which is the first step in the cascade of events that cause atherosclerosis.…”

Type I IFNs Regulate Inflammation, Vasculopathy, and Fibrosis in Chronic Cutaneous Graft-versus-Host Disease

“…Pathologically, scleroderma is characterized by a marked vasculopathy associated with neointimal thickening and capillary rarification. As the disease progresses, the vascular inflammation becomes more fibrotic in nature with the accumulation of extracellular matrix composed of different collagen types, proteoglycans, and elastic fibers such as fibrillin (3,4) The mechanisms that promote immune dysfunction and fibrosis are poorly understood. In recent years, experimental models focusing on the fibrotic remodeling component of SSc have highlighted a role for the TGF-b pathway (5)(6)(7)(8).…”

Potential of fibroblasts to regulate the formation of three-dimensional vessel-like structures from endothelial cells in vitro

“…Mechanistic studies designed to gain a better understanding of, and an ability to manipulate, the angiogenic process in health and disease have intensified during the past 30 years, having been stimulated by Folkman's (2,16,19,25,27) initial hypotheses regarding the angiogenic switch during tumor cell growth and the development of the concept of antiangiogenic therapy. In the interim, a number of angiogenic and angiostatic mediators have been identified, and inhibition of angiogenesis is now a therapeutic strategy implemented for patients with rheumatoid arthritis, cancer, and hypertrophic scarring (4,11,17,41,50), whereas systemic sclerosis as a fibrotic disease with a reduced and insufficient vascular network instead requires the support of EC network formation (9,30). The latter is also true for the remodeling and recovery of vascular structures that are reversibly or apparently irreversibly damaged during various disease states, such as arteriosclerosis or after organ failure.…”