Cellular mechanosignaling in pulmonary arterial hypertension

Fig. 1. Vascular remodeling in pulmonary arterial hypertension is manifested by increased pulmonary arterial pressures, decreased arterial compliance, and pruning of the vasculature. At the cellular level, pulmonary arterial adventitial fibroblasts (PAAFs) respond to increased strain, endothelial cells (PAECs) respond to increased flow, and smooth muscle cells (PASMCs) are activated to contract causing vasoconstriction. These cellular responses feedback into the system by increasing extracellular matrix (ECM) stiffness, releasing paracrine factors, and increasing PA pressure, respectively. Images used with permission from J Signal Transduct. 2012: 951497, and sciencellonline.com

Fig. 2. Increased pulmonary arterial pressure (P) increases vessel wall stress (σ), strain (ε), and blood flow, which increases shear fluid shear stress (τ) on the endothelium. The main cell types affected by these mechanical forces are PAECs — blue PASMCs — red, PAAFs — green

Fig. 3. The effect of an increase of mean pulmonary arterial pressure (mPAP) on increasing blood flow results in increased shear stress experienced by pulmonary arterial endothelial cells (PAECs) which increases their proliferation. This and other cytokines mediate the PAEC transition into activated fibroblasts and release of paracrine factors that induce smooth muscle cell (PASMC) proliferation and vasoconstriction that in turn reduces blood flow. An increase in mPAP also increases PA wall stress and strain, which increases profibrotic adventitial fibroblast (PAAF) expression, increasing ECM stiffness and overall PA stiffness leading to decreased PA wall strain

Fig. 4. Intracellular and intercellular signaling pathways in pulmonary arterial cells regulated by fluid shear stress, stretch, hypoxia and extracellular matrix (ECM) stiffening. PAECs respond to fluid shear stress via vascular endothelial growth factor (VEGF) signaling and bone morphogenic protein (BMP) signaling, to ECM stiffness via VEGF signaling and miR-7, and to hypoxia via platelet-derived growth factor (PDGF) signaling. PASMCs respond to paracrine signals released by the PAEC and ECM stiffness via transforming growth factor beta 1 (TGF-β1), soluble guanylate cyclase (sGC), and endothelin (ET) signaling while responding to hypoxia via dysregulated BMP signaling and increased Notch signaling and transient receptor potential (TRP) channel calcium influx. PAAFs respond to ECM stiffness via TRP influx of calcium, TGF-β1 signaling, and activation of the Hippo pathway via YAP/TAZ transcription factors, to stretch via YAP/TAZ and PDGF signaling, and to hypoxia via reactive oxygen species (ROS) signaling. The four physical stimuli (black) lead to intercellular reactions (gray dashed arrows) and intracellular reactions (solid arrows matching cell color), resulting in phenotypic outputs…