What question did this study set out to answer?

To investigate the effects of doxorubicin exposure on endothelial cells and its paracrine impact on dermal fibroblasts.

March 6, 2026Toxicological Sciences0 citationsOpen Access

Exposure of endothelial cells to Doxorubicin inhibits Extracellular matrix production by dermal fibroblasts in a paracrine manner

ZJZhu JiangAmsterdam University Medical Centers GSGiulia SorrentinoAmsterdam University Medical Centers MPMadalena Lopes Natário PintoAssociation of Dutch Burn Centres

Key Result

Doxorubicin-induced endothelial cells impair dermal fibroblast ECM production by triggering activation, senescence, and increased matrix-degrading enzymes.

Key Points

To investigate the effects of doxorubicin exposure on endothelial cells and its paracrine impact on dermal fibroblasts.
Endothelial cells were treated with doxorubicin.
Conditioned medium from treated endothelial cells was applied to dermal fibroblasts.
Short- and long-term culture observations were conducted.
Cytokine profiling and molecular markers were analyzed.
Doxorubicin induced endothelial-to-mesenchymal transition in endothelial cells.
Fibroblasts showed early activation with increased fibroblast activation protein and α-smooth muscle actin.
Progressive senescence was observed in fibroblasts, marked by elevated p21 and reduced Lamin B1.
ECM formation was impaired with reduced collagen levels and increased expression of matrix-degrading enzymes.
Cytokine analysis indicated reduced IL-1β, CCL2, and CXCL10, with elevated IL-6 levels.

Structured PICO

Population

Human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts

Intervention

Doxorubicin treatment of HUVECs, with conditioned medium applied to dermal fibroblasts for short- and long-term culture

Outcome

Endothelial-to-mesenchymal transition (EndMT) in endothelial cells and paracrine effects on fibroblast activation, senescence, and extracellular matrix (ECM) synthesissurrogate

Doxorubicin induces endothelial dysfunction and pathological paracrine signaling that drives fibroblast senescence and extracellular matrix disruption, highlighting a mechanism for chemotherapy-associated connective tissue damage.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Doxorubicin (Dox) is a potent chemotherapeutic with known vascular toxicity and connective-tissue damage. Endothelial cells (EC) and fibroblasts crosstalk is essential for vascular homeostasis and extracellular matrix (ECM) remodeling. This study aimed to explores whether Dox induces endothelial-to-mesenchymal transition (EndMT) and the paracrine effects of Dox-exposed EC on fibroblasts activation, senescence, and ECM synthesis. Human umbilical vein endothelial cells (HUVECs) were treated with Dox, and conditioned medium (CM) from EC was applied to human dermal fibroblasts for short- and long-term culture. Dox induced EndMT in ECs. Fibroblasts exposed to CM from Dox-treated EC exhibited early activation with increased fibroblast activation protein (FAP) and α-smooth muscle actin (α-SMA) at day 3, followed by a progressive senescent phenotype marked by elevated p21 and reduced Lamin B1 at day 21. ECM formation was impaired, with reduced collagen and increased transcriptional expression of matrix-degrading enzymes (MMP1 and MMP9). Cytokines profiling of the CM revealed decreased interleukin-1β (IL-1β), C-C motif ligand 2 (CCL2) and C-X-C motif ligand 10 (CXCL10), and elevated interleukin-6 (IL-6) levels. These findings demonstrate that exposure of EC to Dox induced endothelial dysfunction and elicited pathological paracrine signaling, driving fibroblast activation, myofibroblast transition, senescence, and ECM disruption. This mechanism may underlie Dox-related skin aging and delayed wound healing and emphasized the importance of endothelial dysfunction in chemotherapy-associated connective tissue damage and impaired repair.

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