March 2022


SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension
Christine Veith, Ipek Vartürk-Özcan, Magdalena Wujak, Stefan Hadzic, Cheng-Yu Wu, Fenja Knoepp, Simone Kraut, Aleksandar Petrovic, Marija Gredic, Oleg Pak, Monika Brosien, Marie Heimbrodt, Jochen Wilhelm, Friederike C. Weisel, Kathrin Malkmus, Katharina Schäfer, Henning Gall, Khodr Tello, Djuro Kosanovic, Akylbek Sydykov, Akpay Sarybaev, Andreas Günther, Ralf P. Brandes, Werner Seeger, Friedrich Grimminger, Hossein A. Ghofrani, Ralph T. Schermuly, Grazyna Kwapiszewska, Natascha Sommer, Norbert Weissmann


In our study, we provide evidence that secreted protein acidic and rich in cysteine (SPARC) is involved in the pathogenesis of human PH and chronic hypoxia-induced PH in mice, most probably by affecting vascular cell function.

In detail, by microarray analyses we identified Sparc as one of the genes down-regulated at all re-oxygenation time points investigated. Intriguingly, SPARC was vice versa upregulated in lungs during development of hypoxia-induced PH in mice as well as in idiopathic pulmonary arterial hypertension (IPAH) patients. SPARC expression in primary human pulmonary arterial smooth muscle cells (PASMC), but not pulmonary microvascular endothelial cells (PMVEC), was induced either by hypoxia in a HIF (hypoxia-inducible factor)-2A-dependent manner or by transforming growth factor (TGF)-β1. In loss of function studies, SPARC silencing increased apoptosis and decreased proliferation. In gain of function studies, elevated SPARC levels induced PASMC but not PMVEC proliferation. Co-culture and conditioned medium experiments revealed that PMVEC-secreted SPARC acts as a paracrine factor triggering PASMC proliferation. In in vivo experiments, AAV-mediated Sparc knockdown in adult mice significantly improved hemodynamic and cardiac function in PH mice.