期刊
FASEB JOURNAL
卷 36, 期 2, 页码 -出版社
WILEY
DOI: 10.1096/fj.202100773RRR
关键词
biomechanics; bioreactor; extracellular matrix degradation; fibrosis; tendon cells; VEGF signaling
资金
- Austrian Agency for International Collaboration in Education and Research [3/18]
- [SPA06/224]
VEGF signaling plays a crucial role in tendon cell biology, potentially contributing to tendon pathologies. VEGFR1, VEGFR2, and VEGFR3 are expressed in murine and human tendon cells. Additionally, VEGFR3 inhibition prevents biomechanical deterioration and matrix damage in tendon cells, suggesting new treatment options for degenerative tendon diseases.
Vascular endothelial growth factor (VEGF) signaling is crucial for a large variety of cellular processes, not only related to angiogenesis but also in nonvascular cell types. We have previously shown that controlling angiogenesis by reducing VEGF-A signaling positively affects tendon healing. We now hypothesize that VEGF signaling in non-endothelial cells may contribute to tendon pathologies. By immunohistochemistry we show that VEGFR1, VEGFR2, and VEGFR3 are expressed in murine and human tendon cells in vivo. In a rat Achilles tendon defect model we show that VEGFR1, VEGFR3, and VEGF-D expression are increased after injury. On cultured rat tendon cells we show that VEGF-D stimulates cell proliferation in a dose-dependent manner; the specific VEGFR3 inhibitor SAR131675 reduces cell proliferation and cell migration. Furthermore, activation of VEGFR2 and -3 in tendon-derived cells affects the expression of mRNAs encoding extracellular matrix and matrix remodeling proteins. Using explant model systems, we provide evidence, that VEGFR3 inhibition prevents biomechanical deterioration in rat tail tendon fascicles cultured without load and attenuates matrix damage if exposed to dynamic overload in a bioreactor system. Together, these results suggest a strong role of tendon cell VEGF signaling in mediation of degenerative processes. These findings give novel insight into tendon cell biology and may pave the way for novel treatment options for degenerative tendon diseases.
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