Myocardial infarction induces endothelial dysfunction with independence of cardiovascular risk factors

IF 9.2 1区医学 Q1 PERIPHERAL VASCULAR DISEASE

Angiogenesis Pub Date : 2025-09-30 DOI:10.1007/s10456-025-10006-8

Francisco Rafael Jimenez-Trinidad, Núria Solanes, Marta Arrieta, Blanca Llonch, Mercè Roqué, Xavier Freixa, Salvatore Brugaletta, Luis Ortega-Paz, Juan José Rodríguez, Pedro Cepas-Guillen, Gemma Vilhaur, Manel Sabaté, Ana Paula Dantas, Olga Tura-Ceide, Montserrat Rigol

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引用次数: 0

Abstract

Aims

Endothelial dysfunction and impaired angiogenesis are hallmarks of ischemic heart disease and critical determinants of adverse cardiovascular outcomes after myocardial infarction (MI). While conventional cardiovascular risk factors (CVRFs) are known contributors, the specific role of MI itself triggering endothelial dysfunction remains unclear. This study aims to assess the direct impact of MI on endothelial function, independent of cardiovascular risk factors, using human and porcine endothelial colony-forming cells (ECFCs) as a surrogate cellular model.

Methods and results

Human ECFCs (hECFCs) were isolated from the peripheral blood of healthy volunteers (Control-hECFCs, n = 6), patients immediately after MI (AMI-hECFCs, n = 6), and patients 6 months after MI (CMI-hECFCs, n = 6). To evaluate the direct effect of MI independently of CVRFs, a porcine model was used: healthy pigs (n = 6) underwent 90 min of myocardial ischemia by coronary balloon occlusion followed by reperfusion. Porcine ECFCs (pECFCs) were isolated before MI (Control-pECFCs) and one month after MI (CMI-pECFCs, n = 6). In vitro, CMI-hECFCs and CMI-pECFCs had delayed colony formation, whereas AMI-hECFCs did not. Morphological alterations were observed in AMI-hECFCs and CMI-hECFCs (area and shape), while only shape changes were found in CMI-pECFCs. Senescence was increased in AMI-hECFCs and CMI-hECFCs, but not in CMI-pECFCs. Elevated oxidative stress was only detected in CMI-hECFCs. Functional angiogenic and proliferative capacities were reduced in AMI-hECFCs, CMI-hECFCs and CMI-pECFCs; however, only CMI-hECFCs and CMI-pECFCs displayed impaired migration. Molecular analysis showed overactivation of the MSK2/MKK3/p53 signalling axis in dysfunctional ECFCs, while synergistic inhibition of the axis partially restored ECFC function.

Conclusions

MI induces sustained ECFC dysfunction independently of cardiovascular risk factors. Targeting the MSK2/MKK3/p53 pathway may be a promising therapeutic strategy to restore endothelial function and improve angiogenesis after MI.

Graphical abstract

查看原文本刊更多论文

心肌梗死诱导内皮功能障碍与心血管危险因素无关。

目的：内皮功能障碍和血管生成受损是缺血性心脏病的标志，也是心肌梗死（MI）后不良心血管结局的关键决定因素。虽然传统的心血管危险因素（cvrf）是已知的因素，但心肌梗死本身引发内皮功能障碍的具体作用尚不清楚。本研究旨在评估心肌梗死对内皮功能的直接影响，独立于心血管危险因素，使用人和猪内皮集落形成细胞（ecfc）作为替代细胞模型。方法和结果：从健康志愿者（对照- hecfc， n = 6）、心肌梗死后立即患者（ami - hecfc, n = 6）和心肌梗死后6个月患者（cmi - hecfc, n = 6）的外周血中分离出人ecfc （hecfc）。为了评估独立于CVRFs的心肌梗死的直接作用，我们采用猪模型：健康猪（n = 6）经冠状动脉球囊闭塞90分钟心肌缺血后再灌注。分别在心肌梗死前（对照- pecfc）和心肌梗死后1个月（cmi - pecfc, n = 6）分离猪ecfc （pecfc）。在体外，cmi - hecfc和cmi - pecfc延缓了菌落的形成，而ami - hecfc则没有。ami - hecfc和cmi - hecfc均发生了形态学改变（面积和形状），而cmi - pecfc仅发生了形状变化。ami - hecfc和cmi - hecfc的衰老增加，而cmi - pecfc的衰老没有增加。氧化应激升高仅在cmi - hecfc中检测到。ami - hecfc、cmi - hecfc和cmi - pecfc的功能性血管生成和增殖能力降低；然而，只有cmi - hecfc和cmi - pecfc表现出迁移受损。分子分析显示，功能失调的ECFC中MSK2/MKK3/p53信号轴过度激活，而该轴的协同抑制部分恢复了ECFC功能。结论：心肌梗死诱导持续ECFC功能障碍独立于心血管危险因素。靶向MSK2/MKK3/p53通路可能是恢复心肌梗死后内皮功能和改善血管生成的一种有前景的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Angiogenesis PERIPHERAL VASCULAR DISEASE-

CiteScore

21.90

自引率

8.20%

发文量

审稿时长

6-12 weeks

期刊介绍： Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.