Mechanobiological Feedback in Pulmonary Vascular Disease

Abstract

Vascular stiffening in the pulmonary arterial bed is increasingly recognized as an early disease marker and contributor to right ventricular workload in pulmonary hypertension. Changes in pulmonary artery stiffness throughout the pulmonary vascular tree lead to physiologic alterations in pressure and flow characteristics that may contribute to disease progression. These findings have led to a greater focus on the potential contributions of extracellular matrix remodeling and mechanical signaling to pulmonary hypertension pathogenesis. Several recent studies have demonstrated that the cellular response to vascular stiffness includes upregulation of signaling pathways that precipitate further vascular remodeling, a process known as mechanobiological feedback. The extracellular matrix modifiers, mechanosensors, and mechanotransducers responsible for this process have become increasingly well-recognized. In this review, we discuss the impact of vascular stiffening on pulmonary hypertension morbidity and mortality, evidence in favor of mechanobiological feedback in pulmonary hypertension pathogenesis, and the major contributors to mechanical signaling in the pulmonary vasculature.

Keywords: YAP/TAZ; cellular mechanosensors; matrix stiffness; mechanotransduction; pulmonary arterial stiffness; pulmonary hypertension; vascular remodeling; vascular stiffness.

FIGURE 1

Pulmonary arterial stiffening in PAH pathogenesis.

FIGURE 2

Mechanisms of mechanobiological feedback.