In systemic sclerosis (SSc), characterised by microvascular changes leading to ischemia and impaired angiogenesis, the lack of an angiogenic response to hypoxia may be due to inappropriate synthesis of angiogenic and angiostatic factors. Tissue kallikrein (t-kallikrein) is a potent angiogenic agent regulating the kallikrein kinin system with kallistatin as its natural inhibitor. T-allikrein is synthesised by endothelial and vascular smooth muscle cells as well as inflammatory cells.
To evaluate, in SSc patients: t-kallikrein and kallistatin levels and their correlation with clinical features and parameters of microvascular involvement; and t-kallikrein expression in the skin of SSc patients.
Serum levels of t-kallikrein and kallistatin (ELISA) were assayed in 43 SSc patients, also evaluated for subsets (dSSc, 11 patients; lSSc, 32 patients), clinical and immunological features and microvascular involvement (ulcers, teleangiectasias, nailfold videocapillaroscopy). Expression of t-kallikrein (immunohistochemistry) was evaluated in biopsies taken from the involved skin of the forearm of six SSc patients (two lSSc and four dSSc) and six controls.
Circulating levels of t-kallikrein were higher in SSc patients than in controls (n = 35) (P < 0.001). No differences in t-kallikrein were detected between lSSc and dSSc. T-kallikrein levels were higher in patients with early (five patients) and active (31 patients) capillaroscopic patterns than in those with a late pattern (seven patients) (P = 0.019 and 0.023). Patients with giant capillaries and capillary micro-hemorrhages (35 patients) had higher t-kallikrein levels than patients with architectural derangement (8 patients) (P = 0.04). Neither differences in kallistatin levels were detected between SSc patients and controls nor between lSSc and dSSc. In control skin samples, t-kallicrein immunoreactivity was shown in endothelial and smooth muscle cells and pericytes of microvessels. In lSSc skin, immunoreaction for t-kallicrein was found in microvascular endothelial cells and in perivascular inflammatory infiltrates present in the papillary dermis near to the dermo-epidermal junction. In dSSc skin, the few remaining vessels showed no immunoreactivity for t-kallicrein, except for the vessels near sweat glands and nerves.
Our findings indicate that both t-kallikrein levels and t-kallikrein skin expression are related to typical SSc microvascular changes as assayed by nail-fold videocapillaroscopy and by immunohistochemistry of skin biopsies.