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Prox1 preserves lymphatic junction integrity to promote cardiac repair after myocardial infarction

ABSTRACT: Recent studies have documented that cardiac lymphatic vessels play key roles in cardiac repair including immune resolution and cardioprotection, positioning cardiac lymphatics as a promising therapeutic target in cardiovascular disease. However, cardiac lymphatic dysfunction, characterized by dilated, leaky vessels and impaired drainage are strongly associated with worsened cardiac outcomes in both experimental models and patients with ischemic heart disease, yet the molecular mechanisms leading to lymphatic dysfunction in the injured heart remain poorly defined. Here we determined how the transcription factor Prox1 preserves lymphatic junctional integrity and drainage function following MI.Using lymphatic-specific Prox1 haploinsufficiency mouse model (Prox1ΔLEC/+), we determined that Prox1ΔLEC/+ mice exhibited worsened cardiac lymphatic drainage function, heightened immune response, increased cardiac fibrosis and aggravated cardiac dysfunction after MI. Injured Prox1ΔLEC/+ hearts displayed dilated, fragmented lymphatic vessels with disrupted VE-Cadherin organization and reduced expressions of the tight junction proteins ZO-1 and Claudin5. PROX1-deficient LECs recapitulated these defects in vitro, exhibiting junctional disorganization and increased intercellular gaps. Mechanistically, PROX1 preserved lymphatic endothelial junctional integrity by regulating VEGFR2/VEGFR3/ERK signaling balance. ERK inhibition restored junctional defects in PROX1-deficienct LECs in vitro, whereas VEGFR2 blockade in vivo improved lymphatic junction organization and reduced macrophage accumulation in Prox1ΔLEC/+ mice after MI. These findings identify a previously unknown PROX1-dependent VEGFR2/VEGFR3/ERK balance controlling lymphatic junction barrier function, and established lymphatic dysfunction as a contributor to adverse cardiac remodeling following MI.

ORGANISM(S): Mus musculus

PROVIDER: GSE345427 | GEO | 2026/09/30

REPOSITORIES: GEO

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Project description:Inflammatory responses are crucial in the pathological cardiac remodeling and repair after myocardial infarction (MI). The lymphatic endothelial cells (LECs) significantly influence immune cell clearance and mitigate cardiac inflammation. Chemokines are known to tightly regulate immune cell mobilization within the infarcted heart, thereby significantly influencing cardiac inflammation and remodeling. However, the role of chemokines expressed by LECs in the regulation of cardiac inflammation post-MI remains unclear. Our study revealed that the expression of CC chemokine CCL2 in cardiac LECs was sharply un-regulated following MI. We thus hypothesized that lymphatic endothelial CCL2 might be involved in post-MI cardiac remodeling. To test this hypothesis, we generated LEC-conditional Ccl2 knock-out mice. In vivo experiments demonstrated that the LEC-Ccl2 deficiency deteriorated cardiac function and worsened adverse cardiac remodeling after MI. Further analysis showed that the loss of CCL2 in LECs impeded post-MI lymphangiogenesis and increased macrophage infiltration in post-MI myocardium and impaired macrophages clearance via afferent cardiac lymphatics. This led to exacerbated inflammatory responses and pathological cardiac remodeling after MI. Mechanistically, our study identified that LECs expressed and secreted CCL2, which played a dual role. LEC-CCL2 recruit macrophages from the infarcted myocardium into the lymphatic system and activated AKT/ETS1 signaling, enhancing VEGFC expression and promoting lymphangiogenesis in an autocrine manner. This study reveals that cardiac LEC-expressing CCL2 tightly control macrophage trafficking via lymphatic vessels in injured hearts and thus diminished post-MI inflammatory responses and lessened adverse cardiac remodeling. This study demonstrates that CCL2 expression in cardiac LECs tightly controls macrophage trafficking via lymphatic vessels in injured hearts, thereby diminishing post-MI inflammatory responses and lessening adverse cardiac remodeling. This study suggests that modulating CCL2 signaling in LECs could provide a promising therapeutic target for resolving excessive inflammation and ameliorating adverse cardiac remodeling after MI.

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Prox1 preserves lymphatic junction integrity to promote cardiac repair after myocardial infarction

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