Mueller Mikala C, Du Yanmei, Walker Lori A, Magin Chelsea M
Department of Bioengineering, University of Colorado, Denver | Anschutz Medical Campus, USA.
Division of Cardiology, Department of Medicine, University of Colorado, Anschutz Medical Campus, USA.
Matrix Biol Plus. 2024 Apr 18;22:100145. doi: 10.1016/j.mbplus.2024.100145. eCollection 2024 Jun.
Respiratory diseases like pulmonary arterial hypertension (PAH) frequently exhibit sexual dimorphism. Female PAH patients are more susceptible to the disease but have increased survival rates. This phenomenon is known as the estrogen paradox, and the underlying mechanisms are not fully understood. During PAH progression in vivo, human pulmonary arterial adventitial fibroblasts (hPAAFs) differentiate into an activated phenotype. These cells produce excess, aberrant extracellular matrix proteins that stiffen the surrounding pulmonary arterial tissues. Here, we employed dynamic poly(ethylene glycol)-alpha methacrylate (PEGαMA)-based biomaterials to study how the age and sex of human serum influenced hPAAF activation in response to microenvironmental stiffening . Results showed female and male cells responded differently to increases in microenvironmental stiffness and serum composition. Male hPAAFs were less activated than female cells on soft hydrogels and more responsive to increases in microenvironmental stiffness regardless of serum composition. Female hPAAF activation followed this pattern only when cultured in younger (age < 50) female serum or when older (age ≥ 50) female serum was supplemented with estradiol. Otherwise, female hPAAF activation was relatively high on both soft and stiffened hydrogels, with little difference in activation between the two conditions. Collectively, these results suggest that it may be possible to model the estrogen paradox observed in PAH and that it is critical for researchers to report cell sex and serum source when conducting experimentation.
像肺动脉高压（PAH）这样的呼吸系统疾病常常表现出性别二态性。女性PAH患者更容易患这种疾病，但生存率更高。这种现象被称为雌激素悖论，其潜在机制尚未完全了解。在体内PAH进展过程中，人肺动脉外膜成纤维细胞（hPAAFs）会分化为活化表型。这些细胞会产生过量、异常的细胞外基质蛋白，使周围的肺动脉组织变硬。在这里，我们使用基于动态聚（乙二醇）-α-甲基丙烯酸酯（PEGαMA）的生物材料来研究人血清的年龄和性别如何影响hPAAFs对微环境硬化的激活。结果表明，雌性和雄性细胞对微环境硬度和血清成分的增加反应不同。在柔软水凝胶上，雄性hPAAFs的活化程度低于雌性细胞，并且无论血清成分如何，对微环境硬度增加的反应更敏感。只有当在较年轻（年龄<50岁）的女性血清中培养或在较年长（年龄≥50岁）的女性血清中添加雌二醇时，雌性hPAAFs的活化才遵循这种模式。否则，雌性hPAAFs在柔软和硬化水凝胶上的活化程度都相对较高，两种条件下的活化差异不大。总体而言，这些结果表明，有可能模拟PAH中观察到的雌激素悖论，并且研究人员在进行实验时报告细胞性别和血清来源至关重要。
