Angiogenesis, the formation of the new blood vessels from pre-existing vasculature, is an essential process occurring under both normal and pathological conditions, such as inflammation and cancer. This complex process is regulated by several cytokines, growth factors and extracellular matrix components modulating endothelial cell and pericyte function. In this study, we discovered that the extracellular matrix glycoprotein Elastin Microfibril Interfacer 2 (Emilin2) plays a prominent role in pericyte physiology. This work was originally prompted by the observations that tumor-associated vessels from Emilin2^−/− mice display less pericyte coverage, impaired vascular perfusion, and reduced drug efficacy, suggesting that Emilin2 could promote vessel maturation and stabilization affecting pericyte recruitment. We found that Emilin2 affects different mechanisms engaged in pericyte recruitment and vascular stabilization. First, human primary endothelial cells challenged with recombinant Emilin2 synthesized and released ∼ 2.1 and 1.2 folds more PDGF-BB and HB-EGF, two cytokines known to promote pericyte recruitment. We also discovered that Emilin2, by directly engaging α₅β₁ and α₆β₁ integrins, highly expressed in pericytes, served as an adhesion substrate and haptotactic stimulus for pericytes. Moreover, Emilin2 evoked increased NCadherin expression via the sphingosine-1-phosphate receptor, leading to enhanced vascular stability by fostering interconnection between endothelial cells and pericytes. Finally, restoring pericyte coverage in melanoma and ovarian tumor vessels developed in Emilin2^−/− mice improved drug delivery to the tumors. Collectively, our results implicate Emilin2 as a prominent regulator of pericyte function and suggest that Emilin2 expression could represent a promising maker to predict the clinical outcome of patients with melanoma, ovarian, and potentially other forms of cancer.

血管生成，即从预先存在的脉管系统形成新血管，是在正常和病理条件（例如炎症和癌症）下发生的重要过程。这一复杂的过程受到多种细胞因子、生长因子和调节内皮细胞和周细胞功能的细胞外基质成分的调节。在这项研究中，我们发现细胞外基质糖蛋白弹性蛋白微原纤维接口 2 (Emilin2) 在周细胞生理学中发挥着重要作用。这项工作最初是由以下观察结果引发的： Emilin2 ^-/−小鼠的肿瘤相关血管表现出周细胞覆盖率较低、血管灌注受损和药物疗效降低，这表明 Emolin2 可以促进影响周细胞募集的血管成熟和稳定。我们发现 Emolin2 影响参与周细胞募集和血管稳定的不同机制。首先，用重组Emilin2攻击的人原代内皮细胞合成并释放了约2.1倍和1.2倍的PDGF-BB和HB-EGF，这两种已知促进周细胞募集的细胞因子。我们还发现Emilin2通过直接结合在周细胞中高表达的α ₅ β ₁和α ₆ β ₁整合素，充当周细胞的粘附底物和趋触刺激物。此外，Emilin2通过 1-磷酸鞘氨醇受体引起 N 钙粘蛋白表达增加，通过促进内皮细胞和周细胞之间的互连来增强血管稳定性。最后，恢复Emilin2 ^−/−小鼠体内黑色素瘤和卵巢肿瘤血管中的周细胞覆盖，改善了肿瘤的药物输送。总的来说，我们的结果表明 Emilin2 是周细胞功能的重要调节因子，并表明 Emilin2 表达可能代表预测黑色素瘤、卵巢癌和潜在其他形式癌症患者临床结果的有前途的标志物。