VEGF-A signalling at the vascular-immune interface: impact of anti-angiogenic agents on cardiovascular homeostasis and anthracycline-induced injury.

backgroundVascular endothelial growth factor A (VEGF-A) signalling is a central regulator of cardiovascular homeostasis, integrating endothelial function, cardiomyocyte survival, and immune cell trafficking. While therapies targeting VEGF-A and its receptors (VEGFRs) have transformed cancer treatment, their interference with physiological vascular signalling contributes to the observed cardiovascular toxicity, particularly when combined with anthracyclines. Emerging evidence indicates that anthracycline-mediated cardiotoxicity extends beyond direct myocardial injury to involve a coordinated activation of innate and adaptive immune pathways. Damage-associated molecular patterns (DAMPs) released by injured cardiomyocytes trigger inflammasome activation, cytokine production, and recruitment of neutrophils, macrophages, and T cells, establishing a sustained inflammatory milieu.

objectiveThis review delineates the role of VEGF-A as a central regulatory hub at the interface of vascular and immune signalling pathways, critically examines its contribution to anthracycline-induced cardiotoxicity, and evaluates the pathophysiological consequences associated with its signalling inhibition.

methodsPreclinical, clinical, and review studies identified in PubMed were analysed to provide an up-to-date overview of: (a) the cardiotoxic effects of anthracyclines, VEGF-A-targeting therapies, and their combination; and (b) the mechanisms underlying immune-mediated responses in anthracycline-induced cardiotoxicity, with particular emphasis on the role of VEGF-A.

resultsUnder physiological conditions, VEGFR-2 signalling preserves endothelial integrity and restrains inflammation, whereas VEGFR-1 regulates immune cell recruitment. Anthracyclines disrupt this balance by suppressing cardioprotective VEGFR-2 pathways while promoting DAMP-driven inflammation. Concomitant VEGF-A/VEGFR-2 inhibition by monoclonal antibodies or by small-molecule kinase inhibitors further exacerbates this imbalance, impairing endothelial repair, enhancing microvascular rarefaction, and amplifying immune activation. This "double hit" paradigm results in a synergistic cardiotoxic insult, characterised by inflammation, metabolic dysfunction, and progressive cardiac remodelling.

conclusionBy integrating molecular, vascular, and immunological mechanisms, this review proposes a unified immune-vascular-cardiac framework to explain cardiotoxicity associated with anthracyclines, anti-VEGF-A therapies, and their combination. Within this framework, dissecting receptor-specific signalling, particularly the distinct roles of VEGFR-1 and VEGFR-2, highlights the advantages of selective receptor modulation. Targeting VEGFR-1 emerges as a promising strategy to mitigate cardiotoxicity while preserving anticancer efficacy. Furthermore, combining these immune-vascular insights with clinical surveillance and pharmacogenetic approaches may support the development of precision cardio-oncology strategies that effectively balance toxicity reduction with therapeutic benefit.