Victoria Anne Flower, Shaney Louise Barratt, Darren John Hart, Jacqueline Anne Shipley, John David Pauling
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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).</p><p><strong>Results: </strong>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-A<sub>165</sub>b 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-A<sub>165</sub>b (+0.709, p = 0.022) than panVEGF-A (+0.552, p = 0.098). Epidermal HIF2α and fibroblast VEGF-A<sub>165</sub>b 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-A<sub>165</sub>b correlated with skin thickness (-0.672, p = 0.006).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":17036,"journal":{"name":"Journal of Scleroderma and Related Disorders","volume":" ","pages":"23971983251344040"},"PeriodicalIF":1.4000,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133783/pdf/","citationCount":"0","resultStr":"{\"title\":\"Examining the relationship between vascular biomarkers and both microangiopathy and cutaneous fibrosis in systemic sclerosis.\",\"authors\":\"Victoria Anne Flower, Shaney Louise Barratt, Darren John Hart, Jacqueline Anne Shipley, John David Pauling\",\"doi\":\"10.1177/23971983251344040\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>The objective of the study is to explore the pathogenic relationship between vasculopathy and fibrosis in systemic sclerosis through expression of vascular biomarkers.</p><p><strong>Methods: </strong>Plasma biomarkers including panVEGF-A, VEGF-A<sub>165</sub>b 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).</p><p><strong>Results: </strong>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-A<sub>165</sub>b 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-A<sub>165</sub>b (+0.709, p = 0.022) than panVEGF-A (+0.552, p = 0.098). Epidermal HIF2α and fibroblast VEGF-A<sub>165</sub>b 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-A<sub>165</sub>b correlated with skin thickness (-0.672, p = 0.006).</p><p><strong>Conclusions: </strong>Increased expression of HIFα and antiangiogenic biomarkers associated with both vasculopathy and fibrosis in systemic sclerosis. 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引用次数: 0
摘要
目的：通过血管生物标志物的表达，探讨系统性硬化症血管病变与纤维化的致病关系。方法：对53例系统性硬化症患者和15例对照组的血浆生物标志物panVEGF-A、VEGF-A165b和血管生成素（angi）及临床参数进行研究。对10例系统性硬化症患者和5例对照患者的皮肤进行活检，评估缺氧诱导因子（HIF1α、-2α）和VEGF-A亚型的表达。血管病变评估采用甲襞毛细血管镜（定性模式和毛细血管间距离），缺血后再灌注梯度和超声血管指数（背掌血管指数）。使用皮肤评分和超声（皮肤厚度、回声性和弹性成像）评估皮肤纤维化。结果：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/-2比值降低（p = 0.018）。Ang-2在甲襞毛细血管镜下呈渐进式升高（p = 0.031），与毛细血管间距离（+0.284,p = 0.05）和再灌注梯度（-0.356,p = 0.018）呈弱相关。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)和弹性学（Ang-2 +0.353, p = 0.014）。血浆VEGF-A165b与背掌血管指数相关（-0.289,p = 0.039）。HIF1α和2α在皮肤中升高（p = 0.008），以HIF2α为主。表皮HIF2α与VEGF-A165b （+0.709, p = 0.022）的相关性强于panVEGF-A （+0.552, p = 0.098）。表皮HIF2α和成纤维细胞VEGF-A165b倾向于与早期弥漫性皮肤系统性硬化症相关。HIF1α (+0.489, p = 0.069)和HIF2α (+0.489, p = 0.064)的皮肤表达与毛细血管间距相关。表皮VEGF-A165b与皮肤厚度相关（-0.672,p = 0.006）。结论：HIFα和抗血管生成生物标志物的表达增加与系统性硬化症的血管病变和纤维化相关。我们的数据突出了双抑制生物标志物如ang2的可能治疗靶点。
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.
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