Volkova Eugenia, Procell Linda, Kong Lingyang, Santhanam Lakshmi, Gerecht Sharon
Department of Chemical and Biomolecular Engineering Johns Hopkins University Baltimore Maryland USA.
Institute for NanoBioTechnology, Johns Hopkins University Baltimore Maryland USA.
Bioeng Transl Med. 2022 Oct 3;8(2):e10403. doi: 10.1002/btm2.10403. eCollection 2023 Mar.
Pulmonary arterial hypertension (PAH) is more prevalent in females than males; the causes of this sex difference have not been adequately explored. Gain-of-function (GOF) mutations in hypoxia-inducible factor 2α (HIF2A) lead to PAH and thrombotic consequences in patients and mice. Additionally, multiple emerging studies suggest that elevated systemic arterial stiffening (SAS) occurs in PAH; this could have critical prognostic value. Here, we utilized a HIF2A GOF mouse model to determine how SAS can be used as a prognosticator in sex-divergent PAH. We analyzed survival, vascular mechanics, and vascular phenotypes in young adult (8-16 weeks) and middle age (9-12 months) Hif2a GOF mice. We find that Hif2a heterozygous (HT) female mice, but not Hif2a HT male mice, exhibit poor survival, SAS upon aging, and decreased ability to withstand repeated physiological strain. Hif2a HT female mice also display thickening of the adventitial intima and increased collagen I and collagen III in all layers of the thoracic aorta. Our findings demonstrate differing PAH progression in female and male Hif2a GOF mice. Specifically, alterations in extracellular matrix (ECM) content led to vascular stiffening in aged females, resulting in poor survival. Moreover, we show that SAS emerges early in mice with PAH by coupling studies of vascular mechanics and analyzing vascular structure and composition. Importantly, we present a model for assessing sex differences in hereditary PAH progression and sex-specific prognosis, proposing that aortic stiffening can be used to prognosticate future poor outcomes in PAH.
肺动脉高压（PAH）在女性中比男性更普遍；这种性别差异的原因尚未得到充分探究。缺氧诱导因子2α（HIF2A）的功能获得性（GOF）突变会导致患者和小鼠出现PAH及血栓形成后果。此外，多项新研究表明，PAH患者存在全身动脉僵硬度（SAS）升高的情况；这可能具有关键的预后价值。在此，我们利用HIF2A GOF小鼠模型来确定SAS如何作为性别差异PAH的预后指标。我们分析了年轻成年（8 - 16周）和中年（9 - 12个月）Hif2a GOF小鼠的生存率、血管力学和血管表型。我们发现，Hif2a杂合（HT）雌性小鼠，但不是Hif2a HT雄性小鼠，表现出较差的生存率、衰老时的SAS以及承受反复生理应激能力的下降。Hif2a HT雌性小鼠还表现出胸主动脉外膜内膜增厚以及胸主动脉各层中I型和III型胶原蛋白增加。我们的研究结果表明，雌性和雄性Hif2a GOF小鼠的PAH进展存在差异。具体而言，细胞外基质（ECM）含量的改变导致老年雌性小鼠血管僵硬，从而导致生存率降低。此外，通过结合血管力学研究和分析血管结构与组成，我们表明SAS在PAH小鼠中早期出现。重要的是，我们提出了一个评估遗传性PAH进展中的性别差异和性别特异性预后的模型，提出主动脉僵硬可用于预测PAH未来的不良结局。
