Volume 4 Issue 10, October 2025

The lymphatic vasculature has emerged as a key component of the heart’s response to injury, influencing both regeneration and maladaptive remodeling. Research now highlights the role of lymphatic clearance in shaping the composition of tissue-resident macrophages within the neonatal heart.

Massively parallel reporter assays (MRPAs) are used in vascular smooth muscle cells to measure the functional effects of over 25,000 variants associated with coronary artery disease. This approach identifies regulatory variants in moderate linkage to disease-associated loci, implicating a broader spectrum of causal variants.

Upregulation of PGC-1α in the mouse heart during exercise training maintains mitochondrial homeostasis and promotes physiological hypertrophy by suppressing the stress-induced production of GDF15 in cardiomyocytes independently of its circulating levels. Identification of this cell-autonomous signaling circuit provides novel insights into the functional role of GDF15 in health and diseases. Future studies are warranted to investigate the interaction of PGC-1α and GDF15 in other stress conditions and in human subjects.

Oxidative phosphorylation was considered detrimental for heart regeneration, as it produces reactive oxygen species that block cardiomyocyte proliferation by causing DNA damage. However, harnessing natural variation in the regenerative capacity of seven wild-type zebrafish strains has revealed that the activation of oxidative metabolism after proliferation is essential for cardiomyocyte maturation and successful regeneration.

Using single-cell and spatial transcriptomics on muscle samples from non-ischemic patients and patients with peripheral artery disease (PAD), Turiel et al. identify cellular and molecular changes in the muscle microenvironment during PAD, focusing on endothelial cell–macrophage interactions.

Weldy et al. show that smooth muscle expression of the RNA editing enzyme ADAR1 regulates activation of the double-stranded RNA sensor MDA5 in a novel mechanism of atherosclerosis.

Chapman, Klaourakis and colleagues reveal that a lymphatic vasculature with poor clearance capacity in perinatal, regeneration-competent mouse hearts is required to retain pro-reparative macrophages and allow cardiac regeneration.

Khetarpal et al. show that the metabolic regulator PGC-1α is essential in heart muscle cells for exercise-driven cardiac growth, and that suppression of the stress-induced myokine GDF15 is required to enable cardiomyocyte adaptations to training.

Barbera et al. identify and map genetic variants that alter the characteristics of vascular smooth muscle cells and contribute to the risk of coronary artery disease.

Mulholland et al. identify progenitor exhausted T cells, expressing intermediate levels of PD-1 (PD-1^int), as a prominent source of pro-inflammatory cytokines in the murine atherosclerotic aorta and potential cellular targets driving checkpoint inhibition-elicited pro-atherosclerotic immune responses. They further demonstrate elevated levels of circulating PD-1-expressing T cells in individuals with subclinical cardiovascular disease.

Lin, Geng and colleagues identify a non-canonical AHR pathway that is activated by canonical AHR inhibitors, promoting the proliferation of quiescent endothelial cells with potential applications in cell therapy.

Wünnemann et al. generate a subcellular resolution spatial map of the murine heart after myocardial infarction, revealing that immune cells can infiltrate the organ through the endocardium.

Lekkos et al. show that a metabolic switch toward oxidative phosphorylation is required for cardiomyocyte re-differentiation and heart regeneration after injury in fish.

Yamazoe et al. show that B cell-derived autoantibodies contribute to the development of atrial fibrillation, suggesting that targeting the humoral immune response may represent a viable therapeutic approach.

Ma et al. demonstrate that air pollution is associated with an increased risk of thoracic aortic aneurysm and dissection (TAAD), and that genetic susceptibility to TAAD amplifies this risk through multiplicative and additive interactions.

Achter et al. established a protocol for quantitative proteomic profiling of formalin-fixed, paraffin-embedded human cardiac tissues, benchmarked against fresh-frozen samples. They applied it to stratify patients with arrhythmogenic cardiomyopathy and performed deep proteomic analysis of the human sinoatrial node.

Guo, Zhao and colleagues use high-resolution 7 T MRI to measure the pulsatility of cerebral small vessels and uncover age-related differences in vascular dynamics, which offer new insights into mechanisms of brain aging and vascular risks.