Abstract
Pulmonary artery (PA) pressure increases during lung growth after unilateral pneumonectomy (PNX). Mechanosensitive transcriptional co-activator, yes-associated protein (YAP1), in endothelial cells (ECs) is necessary for angiogenesis during post-PNX lung growth. We investigate whether increases in PA pressure following PNX control-angiogenesis through YAP1. When hydrostatic pressure is applied to human pulmonary arterial ECs (HPAECs), the expression of YAP1, transcription factor TEAD1, and angiogenic factor receptor Tie2 increases, while these effects are inhibited when HPAECs are treated with YAP1 siRNA or YAP1S94A mutant that fails to bind to TEAD1. Hydrostatic pressure also stimulates DNA synthesis, cell migration, and EC sprouting in HPAECs, while YAP1 knockdown or YAP1S94A mutant inhibits the effects. Gene enrichment analysis reveals that the levels of genes involved in extracellular matrix (ECM), cell adhesion, regeneration, or angiogenesis are altered in post-PNX mouse lung ECs, which interact with YAP1. Exosomes are known to promote tissue regeneration. Proteomics analysis reveals that exosomes isolated from conditioned media of post-PNX mouse lung ECs contain the higher levels of ECM and cell-adhesion proteins compared to those from sham-operated mouse lung ECs. Recruitment of host lung ECs and blood vessel formation are stimulated in the fibrin gel containing exosomes isolated from post-PNX mouse lung ECs or pressurized ECs, while YAP1 knockdown inhibits the effects. These results suggest that increases in PA pressure stimulate angiogenesis through YAP1 during regenerative lung growth.
Highlights
We demonstrate that hydrostatic pressure, which significantly increases after unilateral PNX, stimulates angiogenic activities through endothelial YAP1 signaling
We found that exosomes isolated from conditioned media of post-PNX lung endothelial cells (ECs) or pressurized ECs stimulate blood vessel formation in the fibrin gel implanted on the mouse lungs (Supplementary Figure S5)
Gene enrichment analysis confirms that mechanosensitive genes altered in postPNX mouse lung ECs interact with YAP1
Summary
Compensatory lung growth is induced in the remaining lung tissues after unilateral PNX in humans and other species (e.g., mice, dogs) (Hsia et al, 2001; Sakurai et al, 2007; Ding et al, 2011; Butler et al, 2012; Thane et al, 2014; Mammoto et al, 2016a; Liu et al, 2016; Mammoto T. et al, 2019; Hendee et al, 2021); the remaining alveolar units undergo epithelial and EC proliferation to Mechanosensitive Control of Angiogenesis compensate for the initial loss. Inhibition of angiogenesis impairs compensatory lung growth after PNX in adult mice (Sakurai et al, 2007; Ding et al, 2011; Mammoto et al, 2016a; Mammoto T. et al, 2019; Hendee et al, 2021) Mechanical factors such as ECM stiffness, shear stress, and stretching forces control angiogenesis and vascular function (Mammoto et al, 2009; Thodeti et al, 2009; Mammoto A. et al, 2013; Mammoto T. et al, 2013; Mammoto and Mammoto, 2019). We examined whether increases in PA pressure after PNX stimulate angiogenesis through YAP1
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