Systemic Sclerosis

An Update

Uwe-Frithjof Haustein, MD, PhD


Lab Med. 2011;42(9):562-572. 

In This Article

Endothelial Cells

The role of EC is still poorly understood (Figure 2). On the 1 hand, EC are targets of immune activity. On the other hand, they may act as immune co-stimulators.[34] One hypothesis suggests that SSc starts following repeated insults to the vascular endothelium, in particular after cold exposure. The vascular abnormality may be caused by repeated episodes of vasoconstriction leading to hypoxia, ischemia, and intravascular occlusion. Moreover, an imbalance in endothelial signals (increased vasoconstrictory endothelin release), impaired vasodilatory mechanisms (nitric oxide [NO] corresponding to endothelial dependent relaxation factor [EDRF]), enhanced platelet aggregation, and deficient neuropeptide levels lead to the well recognized vasospastic propensity. The deficient endothelial dependent relaxation in SSc is suggested by impaired maximal responses to endothelial dependent vasodilators such as bradykinin and substance P in conjunction with defective endothelial production of the vasodilator NO.[35] Presumably, the endothelial NO synthase gene expression is inhibited, in particular by TGFβ[36] Thus, the impaired NO production may contribute to platelet activation and to oxidative injury of EC, as well as promote inflammation and enhance the arteriolar internal proliferation in SSc.[37]

Figure 2.

Endothelial Cells in the Pathogenesis of SSc. Endothelial cells can be targeted by various mechanisms such as cold exposure, hypoxia (Raynaud's phenomenon), cytotoxic processes, and toxic factors such as proteases (eg, latent CMV-infection, oxidative stress [lipoperoxides], antibody-dependent cell cytotoxicity [ADCC]), and by Auto-ab like AECA. All of them may lead either to activation of EC (eg, coagulation, PMNC adhesion, FB-proliferation) or to apoptosis of EC. Defective progenitor EC are not able to compensate the damages

Other damaging influences, such as toxic factors, proteases (granzyme 1), lipoperoxides, and IgG antiendothelial Auto-ab may contribute to this process.[38] In addition, SNPs of hypoxia-induced factor (HIF)1A gene are associated with SSc. Although persisting hypoxia is a major stimulus for angiogenesis, it does not occur in SSc, probably due to an insufficient response to the elevated levels of vascular endothelial growth factor (VEGF).[39] The increased release of endothelin, thromboxane, factor VIII antigen, and thrombomodulin are signs of an injury to EC, partly also mediated by anti-endothelial cell antibodies (AECA).[40,41]


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