Faculty Collaboration Database

Characterization of anticancer therapy-induced microvascular dysfunction in patients with breast cancer supports targeted intervention. JCI Insight 2025 Nov 24;10(22)

Date

09/30/2025

Pubmed ID

41026534

Pubmed Central ID

PMC12643535

DOI

10.1172/jci.insight.194316

Scopus ID

2-s2.0-105022722049 (requires institutional sign-in at Scopus site)   4 Citations

Abstract

BACKGROUNDCardiotoxicity is a major complication of anticancer therapy (CTx); however, the effect of CTx on the microcirculation is not well defined. This study evaluated the effect of CTx on microvascular function in patients with breast cancer (PwBC).METHODSEndothelial function and angiogenic potential were assessed in arterioles and adipose biopsies obtained from PwBC undergoing CTx (longitudinal and cross-sectional) and in healthy arterioles exposed to doxorubicin (Dox), trastuzumab (TZM), or paclitaxel (PTX) ex vivo. VEGF-B protein was used to test feasibility of targeted intervention.RESULTSPwBC treated with Dox and/or TZM developed profound microvascular endothelial dysfunction that persisted for ≥ 9 months after treatment cessation. Angiogenic potential was reduced during CTx and recovered within 1 month. Gene expression related to angiogenesis and inflammation changed over the course of clinical treatment. Adipose arterioles from healthy donors developed endothelial dysfunction when exposed to Dox or TZM ex vivo. PTX, which poses minimal cardiovascular risk, had no effect on vasomotor function. Ex vivo exposure to Dox or PTX suppressed angiogenic potential, whereas TZM had no effect. VEGF-B protein preserved endothelial function in arterioles exposed to Dox or TZM ex vivo.CONCLUSIONPwBC undergoing treatment with Dox and/or TZM develop prolonged microvascular endothelial dysfunction that is recapitulated in healthy arterioles exposed to Dox or TZM ex vivo. Targeted intervention with VEGF-B protects against direct Dox- or TZM-induced vascular toxicity in human arterioles ex vivo.FUNDINGNIH, American Heart Association, WeCare Foundation, Medical College of Wisconsin, Advancing a Healthier Wisconsin, Jenny and Antti Wihuri Foundation.

Author List

Terwoord JD, Norwood Toro LE, Hader SN, Hammond ST, Hockenberry JC, Linn J, Vazirabad IY, Kong AL, Kriegel AJ, Liu Z, Kivelä RM, Murtagh G, Gutterman DD, Beyer AM

Authors

Andreas M. Beyer PhD Professor in the Medicine department at Medical College of Wisconsin
David Gutterman MD Emeritus Professor in the Medicine department at Medical College of Wisconsin
Stephen T. Hammond Postdoctoral Researcher 3 in the Medicine department at Medical College of Wisconsin
Amanda L. Kong MS, MD Professor in the Surgery department at Medical College of Wisconsin
Ziqing Liu PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
Ibrahim Y. Vazirabad Bioinformatics Analyst III in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adipose Tissue
Adult
Aged
Antineoplastic Agents
Arterioles
Breast Neoplasms
Cross-Sectional Studies
Doxorubicin
Endothelium, Vascular
Female
Humans
Microcirculation
Microvessels
Middle Aged
Neovascularization, Pathologic
Paclitaxel
Trastuzumab