Angiogenesis and Vasculopathy in Systemic Sclerosis: Evolving Concepts

Abstract

Systemic sclerosis (scleroderma [SSc]) is a multifactorial disease characterized by inflammation, extensive and progressive fibrosis, and multiple vasculopathies. The vascular manifestations can be seen early in the pathogenesis of the disease and include malformed capillaries, Raynaud's phenomenon, and digital ulcers. As the disease progresses, the vasculopathy proceeds to significant clinical manifestations, including renal crisis and pulmonary arterial hypertension. Moreover, later stages of the disease are marked by increasingly avascular areas. Despite the obliteration of microvascular structures, compensatory vasculogenesis and angiogenesis do not occur normally. This is in spite of a general increase in many potent angiogenic factors. Recent studies are beginning to examine this paradox and subsequent paucity of an angiogenic response in SSc. In this review, we discuss these findings and examine the role that chemokine and growth factor receptors, proteases, adhesion molecules, and transcription factors play in the dysregulation of angiogenesis in SSc.

Evaluation of choroidal thickness in patients with scleroderma

“…2 Choroid contains small arterioles and capillaries, and as a result, abnormality in choroidal vasculature may occur in patients with scleroderma. However, there are few studies and case presentations, which have investigated the pathophysiology of choroid and given information about changes in choroid in patients with scleroderma.…”

“…1 Vasculopathy in the scleroderma mainly affects small arteries and capillaries is characterized by obliteration of vessels and reduced capillary density. 2 The most common ocular findings are keratoconjunktivitis sicca, eyelid skin fibrosis, anterior uveitis, normal tension glaucoma, optic neuropathy, and choroidopathy. [3][4][5][6] Choroid is a vascular structure of the eye that supplies oxygen and metabolites to the outer segment of the retina.…”

Potential biomarkers in patients with systemic sclerosis

“…Fibrosis and inflammation are tightly linked in autoimmune diseases and in SSc the functional/structural changes of endothelium are key events, in the development of digital ulcers and skin fibrosis. 1 Among the soluble adhesion molecules, sICAM-1 might reflect the proinflammatory state of endothelium in SSc. This molecule, in addition to being an activation marker, triggers a pro-inflammatory cascade in endothelial cells by inducing cytokine production and over-expression of other adhesion molecules.…”

“…However, paradoxically a deficit of angiogenesis in the skin of these patients has been reported with development of avascular areas in the skin and in the internal organs, leading to digital ulcers, skin and organ fibrosis. 1 The detection of vascular endothelial growth factor (VEGF) in the circulation of SSc patients has given conflicting results, while in some studies VEGF and other pro-angiogenic mediators, such as fibroblast growth factor (FGF)-2 and interleukin (IL)-8, have been shown to be up-regulated; [2][3][4] in others the levels of VEGF were similar to those of healthy controls. 5 Among the antiangiogenic mediators, endostatin (ES), by inhibiting VEGF, is one of the main anti-angiogenic molecules in physiological and pathological conditions.…”

Vasodilatory Therapeutics in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) Cohort

“…Endothelial cell activation and dysfunction are central to the disease pathogenesis and may result in an imbalance of normal vasodilatory and vasoconstrictive mediators synthesized and released by vascular endothelial cells as well as neurological derived vasodilators and vasoconstrictors [1,2]. SSc-vasculopathy manifests as a spectrum of microvascular and macrovascular complications with the most severe and readily visible clinical symptoms being finger-tip digital ulcerations (DU) and pulmonary arterial hypertension (PAH) [3]. PAH is the leading cause of mortality in SSc, thus the role of vasodilatory therapies in SSc could have a major impact on morbidity and mortality [4,5].…”