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.
Highlights
Pulmonary Hypertension is characterized by progressive pulmonary vascular remodeling that leads to exertional dyspnea, severe hypoxemia, and to right heart failure
We have extensively examined the response of pulmonary vascular cells to pathologic matrix stiffness in vitro using discrete stiffness polyacrylamide hydrogels (Liu F. et al, 2010; Liu et al, 2016; Dieffenbach et al, 2017), and have found that stiffness induces changes that can drive further vascular remodeling – a process we call mechanobiological feedback
We have found that stiffnessinduced activation of pulmonary vascular cells is at least in part dependent on downregulation of cyclooxygenase-2 (COX2) expression and Cyclooxygenase 2 (COX-2)-dependent prostanoid production (Fredenburgh et al, 2008; Liu F. et al, 2010; Liu et al, 2016; Dieffenbach et al, 2017)
Summary
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. 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
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