Sonic hedgehog-dependent activation of adventitial fibroblasts promotes neointima formation

Cardiovascular Research
Jochen DutzmannJan-Marcus Daniel

Abstract

Adventitial cells have been suggested to contribute to neointima formation, but the functional relevance and the responsible signalling pathways are largely unknown. Sonic hedgehog (Shh) is a regulator of vasculogenesis and promotes angiogenesis in the adult. Here we show that proliferation of vascular smooth muscle cells (SMC) after wire-induced injury in C57BL/6 mice is preceded by proliferation of adventitial fibroblasts. Simultaneously, the expression of Shh and its downstream signalling protein smoothened (SMO) were robustly increased within injured arteries. In vitro, combined stimulation with Shh and platelet-derived growth factor (PDGF)-BB strongly induced proliferation and migration of human adventitial fibroblasts. The supernatant of these activated fibroblasts contained high levels of interleukin-6 and -8 and strongly induced proliferation and migration of SMC. Inhibition of SMO selectively prevented fibroblast proliferation, cytokine release, and paracrine SMC activation. Mechanistically, we found that PDGF-BB activates protein kinase A in fibroblasts and thereby induces trafficking of SMO to the plasma membrane, where it can be activated by Shh. In vivo, SMO-inhibition significantly prevented the proliferation of a...Continue Reading

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Citations

Jan 4, 2020·European Heart Journal·Stevan D StojanovićDaniel G Sedding
Jun 27, 2019·International Journal of Molecular Sciences·Candice ChapoulyMarie-Ange Renault
Feb 26, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Xingli Xu (徐兴丽)Cheng Zhang (张澄)
Dec 24, 2019·The American Journal of Pathology·Maria G Tinajero, Avrum I Gotlieb
Feb 26, 2021·International Immunopharmacology·Atefe Ghamar TalepoorMehrnoosh Doroudchi
Mar 12, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Anton G KutikhinGuido Krenning
Apr 3, 2021·Annals of Diagnostic Pathology·Simon ParreauKim-Heang Ly
Oct 1, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Chien-Jung LinRobert P Mecham

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