4.7 Article

Doxorubicin Impairs Smooth Muscle Cell Contraction: Novel Insights in Vascular Toxicity

期刊

出版社

MDPI
DOI: 10.3390/ijms222312812

关键词

doxorubicin; cardio-oncology; arterial stiffness; endothelial dysfunction; vascular smooth muscle cell contraction; non-selective cation channel

资金

  1. Fund for Scientific Research (FWO) Flanders [1S33720N, 11C6321N, 1S24720N]
  2. FWO Flanders [1804320N]
  3. DOCPRO4 grant of the Research Council of the University of Antwerp [39984]
  4. INSPIRE project from the European Union's Horizon 2020 Research and Innovation Program (H2020-MSCA-ITN program) [858070]
  5. Marie Curie Actions (MSCA) [858070] Funding Source: Marie Curie Actions (MSCA)

向作者/读者索取更多资源

Chemotherapeutic doxorubicin has been shown to increase arterial stiffness, possibly by reducing vascular smooth muscle cell contraction and Ca2+ influx through Ca2+ channels. However, the specific mechanism remains unclear and requires further investigation. Interestingly, doxorubicin decreased ex vivo arterial stiffness but had minimal effects in vivo, emphasizing the importance of timing in evaluating arterial stiffness in doxorubicin-treated patients.
Clinical and animal studies have demonstrated that chemotherapeutic doxorubicin (DOX) increases arterial stiffness, a predictor of cardiovascular risk. Despite consensus about DOX-impaired endothelium-dependent vasodilation as a contributing mechanism, some studies have reported conflicting results on vascular smooth muscle cell (VSMC) function after DOX treatment. The present study aimed to investigate the effects of DOX on VSMC function. To this end, mice received a single injection of 4 mg DOX/kg, or mouse aortic segments were treated ex vivo with 1 mu M DOX, followed by vascular reactivity evaluation 16 h later. Phenylephrine (PE)-induced VSMC contraction was decreased after DOX treatment. DOX did not affect the transient PE contraction dependent on Ca2+ release from the sarcoplasmic reticulum (0 mM Ca2+), but it reduced the subsequent tonic phase characterised by Ca2+ influx. These findings were supported by similar angiotensin II and attenuated endothelin-1 contractions. The involvement of voltage-gated Ca2+ channels in DOX-decreased contraction was excluded by using levcromakalim and diltiazem in PE-induced contraction and corroborated by similar K+ and serotonin contractions. Despite the evaluation of multiple blockers of transient receptor potential channels, the exact mechanism for DOX-decreased VSMC contraction remains elusive. Surprisingly, DOX reduced ex vivo but not in vivo arterial stiffness, highlighting the importance of appropriate timing for evaluating arterial stiffness in DOX-treated patients.

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