Angiogenesis is a hallmark of fibrocalcific aortic valve disease (CAVD). An imbalance of pro- and anti-angiogenic factors is thought to play a role in driving this disease process, and valvular interstitial cells (VICs) may act as a significant source of these factors. CAVD is also known to exhibit sexual dimorphism in its presentation, and previous work suggested that VICs may exhibit cellular-scale sex differences in the context of angiogenesis. The current study sought to investigate the production of angiogenesis-related factors by male and female VICs possessing quiescent (qVIC) or activated (aVIC) phenotypes. Production of several pro-angiogenic growth factors was elevated in porcine aVICs relative to qVICs, with sex differences found in both the total amounts secreted and their distribution across media vs. lysate. Porcine valvular endothelial cells (VECs) were also sex-separated in culture and found to behave similarly with respect to metabolic activity, viability, and tubulogenesis, but male VECs exhibited higher proliferation rates than female VECs. VECs responded to sex-matched media conditioned by VICs with increased tubulogenesis, but decreased proliferation, particularly upon treatment with aVIC-derived media. It is likely that this attenuation of proliferation resulted from a combination of decreased basic fibroblast growth factor and increased thrombospondin-2 (TSP2) secreted by aVICs. Overall, this study indicates that VICs regulate angiogenic VEC behavior via an array of paracrine molecules, whose secretion and sequestration are affected by both VIC phenotype and sex. Moreover, strong sex differences in TSP2 secretion by VICs may have implications for understanding sexual dimorphism in valve fibrosis, as TSP2 is also a powerful regulator of fibrosis.

中文翻译：

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瓣膜间质细胞的血管生成分泌谱随细胞性别和表型的不同而变化。


血管生成是纤维钙化性主动脉瓣疾病（CAVD）的标志。促血管生成因子和抗血管生成因子的不平衡被认为在驱动这种疾病过程中发挥了作用，瓣膜间质细胞（VIC）可能是这些因子的重要来源。众所周知，CAVD 在其表现上表现出性别二态性，之前的研究表明，VIC 可能在血管生成的背景下表现出细胞规模的性别差异。目前的研究旨在调查具有静止（qVIC）或激活（aVIC）表型的男性和女性VIC产生血管生成相关因子。与 qVIC 相比，猪 aVIC 中几种促血管生成生长因子的产量有所增加，分泌总量及其在培养基和裂解液中的分布均存在性别差异。猪瓣膜内皮细胞 (VEC) 在培养中也进行了性别分离，发现其在代谢活性、活力和肾小管发生方面表现相似，但雄性 VEC 比雌性 VEC 表现出更高的增殖率。 VEC 对 VIC 调节的性别匹配培养基做出反应，管状发生增加，但增殖减少，特别是在使用 aVIC 衍生培养基处理后。这种增殖减弱很可能是由 aVIC 分泌的碱性成纤维细胞生长因子减少和血小板反应蛋白 2 (TSP2) 增加共同造成的。总体而言，这项研究表明，VIC 通过一系列旁分泌分子调节血管生成 VEC 行为，其分泌和隔离同时受到 VIC 表型和性别的影响。此外，VIC 分泌 TSP2 的强烈性别差异可能对理解瓣膜纤维化中的性别二态性具有影响，因为 TSP2 也是纤维化的强大调节剂。