Extracellular Vesicles (EVs) Derived from Senescent Endothelial Cells Promote Platelet Activation

TL;DR

Senescent endothelial cells release EVs that enhance platelet activation, potentially increasing the risk of blood clots in cancer patients treated with Doxorubicin.

Contribution

EVs from senescent endothelial cells promote platelet activation independently of their concentration or size.

Findings

Doxorubicin induces senescence and endothelial dysfunction in HMEC-1 cells.

EVs from senescent cells more strongly activate platelets than those from non-senescent cells.

EVs alone do not cause platelet aggregation, indicating a need for soluble factors.

Abstract

Thrombotic cardiovascular diseases are frequent side effects of cancer therapy with cytotoxic drugs such as Doxorubicin. Endothelial cell senescence is emerging as a critical mechanism underlying endothelial dysfunction in this context. Senescent cells, although unable to proliferate, secrete bioactive molecules that alter the tissue microenvironment, a feature known as the senescence-associated secretory phenotype (SASP). Besides soluble molecules, senescent cells also release extracellular vesicles (EVs). Previous studies indicate that senescent endothelial cells produce a secretome that promotes platelet activation; however, the contribution of EVs remains unclear. Here, we show that human microvascular endothelial cells (HMEC-1) exposed to Doxorubicin undergo senescence, display endothelial dysfunction, and release EVs. We found no differences in the concentration or size distribution of EVs from senescent and non-senescent cells. Nevertheless, EVs from senescent HMEC-1 promoted platelet activation more strongly than EVs from control cells. Notably, EVs alone did not induce platelet aggregation, suggesting that soluble factors are also required to support platelet-dependent hemostasis. These findings reveal that EVs from senescent endothelial cells contribute to platelet activation, a process that may favor thrombosis in patients receiving Doxorubicin-based chemotherapy.

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