Cross-talk between TSC2 and the extracellular matrix controls pulmonary vascular proliferation and pulmonary hypertension

Increased proliferation and survival of cells in small pulmonary arteries (PAs) drive pulmonary arterial hyperten-sion (PAH). Because cell growth mediated by the mTOR-containing mTORC1 complex is inhibited by tuberous sclerosis complex 2 (TSC2), we investigated the role of this GTPase-activating protein in PAH pathology. TSC2 abundance was decreased in remodeled small PAs and PA vascular smooth muscle cells (PAVSMCs) from patients with PAH or from rodent pulmonary hypertension (PH) models, as well as PAVSMCs maintained on substrates that reproduced pathology-induced stiffness. Accordingly, mice with smooth muscle-specific reduction in TSC2 developed PH. At the molecular level, decreased TSC2 abundance led to stiffness-induced PAVSMC proliferation, increased abundance of the mechanosensitive transcriptional coactivators YAP/TAZ, and enhanced mTOR kinase activity. Moreover, extracellular matrix (ECM) produced by TSC2-deficient PAVSMCs stimulated the pro-liferation of nondiseased PA adventitial fibroblasts and PAVSMCs through fibronectin and its receptor, the alpha 5 beta 1 integrin. Reconstituting TSC2 in PAVSMCs from patients with PAH through overexpression or treatment with the SIRT1 activator SRT2104 decreased YAP/TAZ abundance, mTOR activity, and ECM production, as well as inhib-ited proliferation and induced apoptosis. In two rodent models of PH, SRT2104 treatment restored TSC2 abun-dance, attenuated pulmonary vascular remodeling, and ameliorated PH. Thus, TSC2 in PAVSMCs integrates ECM composition and stiffness with pro-proliferative and survival signaling, and restoring TSC2 abundance could be an attractive therapeutic option to treat PH.

Automated summary

This study found that TSC2 abundance is decreased in pulmonary arterial hypertension (PAH) patients, and the loss of TSC2 leads to increased proliferation and survival of vascular smooth muscle cells. The study also found that extracellular matrix produced by remodeled cells stimulates the proliferation of other cells. Restoring TSC2 abundance can inhibit cell proliferation and induce cell apoptosis, providing a potential therapeutic option for treating PAH.