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.