Flower Victoria Anne, Barratt Shaney Louise, Hart Darren John, Shipley Jacqueline Anne, Pauling John David
Department of Rheumatology, Royal National Hospital for Rheumatic Diseases, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK.
Department of Life Sciences, University of Bath, Bath, UK.
J Scleroderma Relat Disord. 2025 Jun 3:23971983251344040. doi: 10.1177/23971983251344040.
The objective of the study is to explore the pathogenic relationship between vasculopathy and fibrosis in systemic sclerosis through expression of vascular biomarkers.
Plasma biomarkers including panVEGF-A, VEGF-Ab 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).
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-Ab 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-Ab (+0.709, p = 0.022) than panVEGF-A (+0.552, p = 0.098). Epidermal HIF2α and fibroblast VEGF-Ab 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-Ab correlated with skin thickness (-0.672, p = 0.006).
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.
本研究旨在通过血管生物标志物的表达，探讨系统性硬化症中血管病变与纤维化之间的致病关系。
对53例系统性硬化症患者和15例对照者进行了包括全血管内皮生长因子-A（panVEGF-A）、血管内皮生长因子-A抗体（VEGF-Ab）和血管生成素（Ang）在内的血浆生物标志物及临床参数的研究。取10例系统性硬化症患者和5例对照者的受累皮肤活检组织，评估缺氧诱导因子（HIF1α、-2α）和VEGF-A亚型的表达。采用甲襞毛细血管镜检查（定性模式和毛细血管间距）、缺血激发后的再灌注梯度以及超声血管指数（背腹血管指数）评估血管病变。采用皮肤评分和超声检查（皮肤厚度、回声性和弹性成像）评估皮肤纤维化。
与对照组相比，系统性硬化症患者血浆Ang-2升高（p = 0.012），Ang-1/Ang-2比值降低（p = 0.018）。Ang-2在甲襞毛细血管镜检查模式中逐渐升高（p = 0.031），与毛细血管间距呈弱相关（+0.284，p = 0.05），与再灌注梯度呈负相关（-0.356，p = 0.018）。血浆血管生成素与回声性相关（Ang-1 +0.381，p = 0.006；Ang-2 +0.330，p = 0.022），与弹性成像相关（Ang-2 +0.353，p = 0.014）。血浆VEGF-Ab与背腹血管指数呈负相关（-0.289，p = 0.039）。皮肤中HIF1α和2α升高（p = 0.008），以HIF2α为主。表皮HIF2α与VEGF-Ab的相关性（+0.709，p = 0.022）比与panVEGF-A的相关性（+0.552，p = 0.098）更强。表皮HIF2α和成纤维细胞VEGF-Ab倾向于与早期弥漫性皮肤系统性硬化症相关。皮肤中HIF1α（+0.489，p = 0.069）和HIF2α（+0.489，p = 0.064）的表达与毛细血管间距相关。表皮VEGF-Ab与皮肤厚度呈负相关（-0.672，p = 0.006）。
系统性硬化症中HIFα和抗血管生成生物标志物的表达增加，与血管病变和纤维化均相关。我们的数据突出了Ang-2等双重抑制生物标志物作为潜在治疗靶点的可能性。
