Inhibition of angiogenesis by platelets in systemic sclerosis patients

Abstract

IntroductionSystemic sclerosis (SSc) is a chronic autoimmune disease characterized by microvascular damage, inflammation, and fibrosis. It has become increasingly evident that platelets, beyond regulating hemostasis, are important in inflammation and innate immunity. Platelets may be an important source of proinflammatory and profibrotic cytokines in the vascular microenvironment. In this study, we sought to assess the contribution of platelet-derived factors in patients with SSc to the angiogenesis of human dermal microvascular endothelial cells (DMVECs) in a tubule formation assay and to characterize the secretion of profibrotic and proinflammatory cytokines in these platelets.MethodsWe analyzed platelets obtained from 30 patients with SSc and 12 healthy control subjects. Angiogenesis was evaluated in vitro with a DMVEC tubule formation assay on Matrigel and platelet-derived angiogenic factors such as vascular endothelial growth factor (VEGF), 165b isoform (VEGF165b), and cytokine secretion was evaluated. Platelet serotonin content was also determined.ResultsWhen DMVECs were incubated with SSc platelet releasates, tubule formation was significantly inhibited (p < 0.01, t test), and higher expression of endothelin-1 in these cells was observed compared with control subjects (p < 0.05, Mann–Whitney U test). In SSc platelet releasates, VEGF165b was significantly higher (p < 0.05, t test), and the VEGF165b/VEGF ratio was increased compared with that of control subjects. Higher secretion of transforming growth factor β (p < 0.01, t test) and CD40L (p < 0.01, t test) was observed compared with control subjects. Also, intraplatelet serotonin levels were lower in platelets obtained from patients with diffuse SSc compared with patients with limited SSc and control subjects (p < 0.05, t test).ConclusionsOur findings suggest that antiangiogenic factors such as VEGF165b, together with proinflammatory and profibrotic factors secreted by platelets, can contribute to the progression of peripheral microvascular damage, defective vascular repair, and fibrosis in patients with SSc.

Serotonin: A Potent Immune Cell Modulator in Autoimmune Diseases

“…Plasma 5-HT content is increased in SSc has been reported (81). Another study revealed that intraplatelet 5-HT content is decreased in patients with diffuse SSc compared with that in patients with limited SSc and normal individuals (82). This indicates that the type of SSc also affects the distribution of 5-HT.…”

Differential Expression of VEGF-Axxx Isoforms Is Critical for Development of Pulmonary Fibrosis

“…The isoform production switch, altering the ratio of VEGF-A xxx a to VEGF-A xxx b, could be viewed as a contributor to disease, or as a protective response of the ATII and other cells, a regulatory mechanism to maintain homeostasis as we have previously postulated in the lung (10) and others in systemic sclerosis (52,53). Interestingly, it has become clear that IPF is associated with multiple splicing changes, such as that required for VEGF-A 165 b (54,55).…”

The Role of Vascular Endothelial Growth Factor in Systemic Sclerosis

“…Platelets are an important source of circulating panVEGF-A in SSc [91] and recent investigation has also proven them to be an important source of VEGF-A165b [92]. Furthermore, tubule formation by dermal MVEC in vitro is impaired when incubated with SSc platelet releasate [92] potentially due to the antiangiogenic action of VEGF-A165b. It is not known whether the platelet load of VEGF-Axxxa/xxxb isoforms remains consistently elevated in SSc or whether isoform switching occurs at some stage in the disease course.…”

“…Figure 3 demonstrates the pathway of hypoxia induced VEGF-A induction via HIF and hypoxia mRNA stabilization [32,43,53,104]. Known cellular sources of VEGF-A in SSc are illustrated based on available evidence (panVEGF-A = (a), VEGF-A165b = (b)) [11,12,89,91,92,103,111,114,131]. *TGFβ and HIF1α synergistically increase VEGF-A in endothelial cells [104].…”