Microvascular Toxicity in Chemotherapy: miRNA Drivers and Anti-miRNA Therapeutic Potential

Background: Cardiovascular toxicity is a major, often irreversible consequence of cancer therapy (CTx) and a leading contributor to morbidity and mortality in cancer survivors. While work has traditionally focused on myocardial injury, microvascular (MV) and endothelial cell (EC) dysfunction, key predictors of major adverse cardiovascular events (MACE), remain poorly characterized despite their essential roles in tissue perfusion and homeostasis. Mechanistic insight into CTx-induced MV injury is urgently needed. To identify circulating regulators linked to vascular vulnerability during CTx, we performed a plasma miRNA screen in breast cancer patients who received CTx and either developed or did not develop MACE. This analysis identified four miRNAs—miR-27a, miR-92a, miR-130a, and miR-331—significantly enriched in patients who developed MACE. Several have known roles in endothelial dysfunction, angiogenesis, and inflammatory signaling, supporting their potential contribution to MV injury during CTx, while others may represent previously unrecognized mediators. Importantly, their selective enrichment in patients with MACE also highlights these miRNAs as potential circulating biomarkers of CTx-induced endothelial dysfunction and cardiovascular risk. Leveraging these candidates, we investigated how these miRNAs influence human MV resilience during CTx exposure. Using isolated human arterioles, we assessed CTx-induced EC and MV dysfunction following miRNA treatment to determine whether they sensitize the MV to injury. Additionally, since anti-miRNA therapeutics are already advancing through clinical trials for other diseases, these studies also explore whether targeted inhibition of circulating miRNAs could represent a viable strategy to preserve MV function and reduce cardiovascular complications during CTx. Hypothesis: We hypothesize that the miRNAs impair microvascular vasodilation during CTx exposure, and that anti-miR treatment will protect the MV from CTx-induced dysfunction. Methods: Subcutaneous adipose arterioles were isolated for two complementary approaches. 1. miRNA + CTx (Healthy Donors): Vessels were treated intraluminally with individual miRNAs (50 nM, ~48 hr) and exposed to paclitaxel (PTX, 1 μM, ~24 hr). 2. Anti-miRNA Treatment (CTx-Exposed Patients): Arterioles from patients with a cancer diagnosis and recent CTx exposure were treated with corresponding anti-miRs (50 nM, ~48 hr).Endothelial function was assessed by flow-mediated dilation (FMD) and acetylcholine (ACh) dose-response curves; smooth muscle function was evaluated using papaverine (Pap). Data are presented as %Max-diameter ±SEM, N with significance defined *P< 0.05 2-way-ANOVA-RM. Results: MV function was significantly altered by miRNA exposure and improved by miRNA inhibition. In healthy donor arterioles, pretreatment with miRNAs, 27a (15±4*, n=3), 130a (49±2*, n=3), 331 (36±4*, n=3), markedly reduced FMD during PTX exposure compared with PTX alone (84±5, n=3), confirming their ability to exacerbate CTx-induced MV dysfunction. Conversely, in arterioles from CTx-exposed cancer patients, anti-miR-92a (78±3*, n=3) significantly restored vasodilation relative to untreated vessels (35±9, n=3), indicating partial rescue of CTx-induced endothelial impairment. Pap-induced dilation was unchanged in all groups. Conclusion: These findings demonstrate that the selected miRNAs directly exacerbate MV dysfunction during CTx exposure, whereas targeted inhibition with anti-miRs restores MV function. Modulating this pathway represents a promising and translatable strategy to reduce MACE risk and improve cardiovascular outcomes in cancer patients receiving CTx. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.