Pulmonary arterial hypertension (PAH) is a deadly pulmonary vascular disease with enigmatic molecular origins. PAH is characterized by an intense remodeling of the pulmonary arterial wall, as well as inflammation and fibrosis throughout the vasculature. Pulmonary arterial remodeling is driven by an excessive proliferation of multiple vascular cell types, leading to increased pulmonary vascular resistance, and ultimately, to severe right-sided heart failure. There exist over a dozen approved pulmonary vasodilatory therapies for PAH which provide symptomatic relief and slow down PAH progression, however, none of them prevents it – or even more cures it – by targeting its molecular origins. The extracellular matrix (ECM) is the principal extracellular component of all tissues and organs. It provides the scaffold that gives physical support to cells and regulates intercellular biochemical and biomechanical signaling. The organization and composition of ECM is not static; it is a dynamic structure. Disruptions and perturbations of this network result in a loss of cell and tissue homeostasis and lead to several diseases. Recently, we reported that activation of resident adventitial fibroblasts drives ECM remodeling to promote pulmonary vascular dysfunction in PAH. Yet, beyond collagen and elastin production, activated fibroblasts produce and secrete hundreds of ECM proteins. Whether and how these proteins affect vascular wall structure and reprogram vascular cells to promote PAH remain unknown.

Here, using a combination of transdisciplinary approaches including primary vascular cells co-culture, confocal microscopy, proteomics, metabolomics, and transcriptomics, we propose to elucidate the unexplored role of ECM biochemical properties variations in vascular cells reprogramming during PAH progression.

Our preliminary data identify Nidogen-2 (NID2) as a key ECM protein upregulated in multiple PAH models and human subjects. Results from ECM synthesized by engineered fibroblasts indicate that modulating NID2 reprograms vascular cells’ proliferation and metabolism.

We hypothesize that increased perivascular NID2 protein level reprograms pulmonary vascular cells’ behavior to promote PAH. By unveiling the crucial role of NID2 during PAH development as a lynchpin connecting vascular wall structure and vascular cells behaviors, we will provide critical insights into the molecular underpinning of PAH with new therapeutic perspectives.