Biologic mechanisms and consequences of pulmonary artery stiffening in pulmonary hypertension

Vascular stiffening in distal pulmonary arteries plays a key role in the early pathogenesis and progression of pulmonary arterial hypertension (PAH). Pathophysiologic cellular responses to vascular stiffness include upregulation of signaling pathways that promote further vascular remodeling, a process known as mechanobiological feedback. Inflammatory signaling and metabolic shifts, particularly upregulation of aerobic glycolysis and glutaminolysis, have also recently been shown to occur downstream of pulmonary vascular stiffening, and are known to play a critical role in PAH development. In this chapter, we will focus on the specific mechanisms underlying these cellular responses. Vascular cell mechanosensing involves the integration of signals from the cell surface, relayed by molecules such as integrins, small GTPases, membrane-associated kinases, and the actin cytoskeleton, into a downstream transcriptional program via nuclear-cytosolic shuttling proteins. Targeting these mechanosensing pathways offers the potential to disrupt mechanobiological feedback and prevent or reverse pathologic pulmonary vascular remodeling in PAH.