Examining the relationship between vascular biomarkers and both microangiopathy and cutaneous fibrosis in systemic sclerosis

Objective:
The objective of the study is to explore the pathogenic relationship between vasculopathy and fibrosis in systemic sclerosis through expression of vascular biomarkers.

Methods:
Plasma biomarkers including panVEGF-A, VEGF-A₁₆₅b and angiopoietins (Ang) and clinical parameters were investigated in 53 systemic sclerosis patients and 15 controls. Biopsies of affected skin from 10 systemic sclerosis patients and 5 controls were used to assess expression of hypoxia-inducible factor (HIF1α, -2α) and VEGF-A isoforms. Vasculopathy was assessed using nailfold capillaroscopy (qualitative pattern and intercapillary distance), reperfusion gradient after ischaemic challenge and ultrasound vascularity index (dorsovolar vascularity index). Skin fibrosis was assessed using skin scores and ultrasound (skin thickness, echogenicity and elastography).

Results:
Plasma Ang-2 was increased (p = 0.012) and Ang-1/-2 ratio reduced (p = 0.018) in systemic sclerosis patients compared to controls. Ang-2 progressively increased across nailfold capillaroscopy patterns (p = 0.031) and weakly correlated with intercapillary distance (+0.284, p = 0.05) and reperfusion gradient (-0.356, p = 0.018). Plasma angiopoietins correlated with echogenicity (Ang-1 +0.381, p = 0.006; Ang-2 +0.330, p = 0.022) and elastography (Ang-2 +0.353, p = 0.014). Plasma VEGF-A₁₆₅b correlated with dorsovolar vascularity index (-0.289, p = 0.039). HIF1α and 2α were increased in skin (p = 0.008) with HIF2α predominance. Epidermal HIF2α correlated more strongly with VEGF-A₁₆₅b (+0.709, p = 0.022) than panVEGF-A (+0.552, p = 0.098). Epidermal HIF2α and fibroblast VEGF-A₁₆₅b tended to associate with early and diffuse cutaneous systemic sclerosis. Cutaneous expression of HIF1α (+0.489, p = 0.069) and HIF2α (+0.489, p = 0.064) correlated with intercapillary distance. Epidermal VEGF-A₁₆₅b correlated with skin thickness (-0.672, p = 0.006).

Conclusions:
Increased expression of HIFα and antiangiogenic biomarkers associated with both vasculopathy and fibrosis in systemic sclerosis. Our data highlight the conceivable therapeutic targets of dual inhibitory biomarkers such as Ang-2.