PHibulin-2

Pulmonary hypertension (PH) is a deadly enigmatic disease with substantial unmet medical needs. PH is characterized by the dysregulation of multiple vascular cell types and is accompanied by inflammation and fibrosis throughout the vasculature. We reported that activation of resident adventitial fibroblasts drives extracellular matrix (ECM) remodeling and vascular stiffness, leading to pulmonary vascular dysfunction. Beyond collagen and elastin production, activated fibroblasts produce and secrete hundreds of ECM proteins. Whether and how these proteins affect vascular wall structure and thus reprogram vascular cells to promote PH remains unknown. Using a quantitative label-free proteomics screening, we identified fibulin-2 (FBLN2) as an essential ECM protein modulated in multiple PH models and human subjects. We also made the unexpected discovery that FBLN2 modulation does not affect matrix stiffness, but reducing the FBLN2 protein level in the ECM broadly rewires the metabolism of vascular cells. Therefore, using a unique combination of primary pulmonary vascular cells, gold-standard preclinical models of PH, and human tissues, we propose to comprehensively decipher the role of FBLN2 in PH and associated metabolic disorders.