Endothelial cell Piezo1 mediates pressure-induced lung vascular hyperpermeability via disruption of adherens junctions.

Proc Natl Acad Sci U S A 2019 Jun 11;116(26):12980-12985. Epub 2019 Jun 11.

Department of Pharmacology, University of Illinois College of Medicine, University of Illinois at Chicago, Chicago, IL 60612;

Increased pulmonary microvessel pressure experienced in left heart failure, head trauma, or high altitude can lead to endothelial barrier disruption referred to as capillary "stress failure" that causes leakage of protein-rich plasma and pulmonary edema. However, little is known about vascular endothelial sensing and transduction of mechanical stimuli inducing endothelial barrier disruption. Piezo1, a mechanosensing ion channel expressed in endothelial cells (ECs), is activated by elevated pressure and other mechanical stimuli. Here, we demonstrate the involvement of Piezo1 in sensing increased lung microvessel pressure and mediating endothelial barrier disruption. Studies were made in mice in which Piezo1 was deleted conditionally in ECs ( ), and lung microvessel pressure was increased either by raising left atrial pressure or by aortic constriction. We observed that lung endothelial barrier leakiness and edema induced by raising pulmonary microvessel pressure were abrogated in mice. Piezo1 signaled lung vascular hyperpermeability by promoting the internalization and degradation of the endothelial adherens junction (AJ) protein VE-cadherin. Breakdown of AJs was the result of activation of the calcium-dependent protease calpain and degradation of the AJ proteins VE-cadherin, β-catenin, and p120-catenin. Deletion of Piezo1 in ECs or inhibition of calpain similarly prevented reduction in the AJ proteins. Thus, Piezo1 activation in ECs induced by elevated lung microvessel pressure mediates capillary stress failure and edema formation secondary to calpain-induced disruption of VE-cadherin adhesion. Inhibiting Piezo1 signaling may be a useful strategy to limit lung capillary stress failure injury in response to elevated vascular pressures.

Download full-text PDF

Source
http://www.pnas.org/lookup/doi/10.1073/pnas.1902165116
Publisher Site
http://dx.doi.org/10.1073/pnas.1902165116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600969PMC
June 2019
12 Reads

Publication Analysis

Top Keywords

microvessel pressure
20
endothelial barrier
16
lung microvessel
12
barrier disruption
12
mechanical stimuli
8
vascular hyperpermeability
8
endothelial
8
capillary stress
8
stress failure
8
lung vascular
8
mice piezo1
8
pulmonary microvessel
8
piezo1
8
pressure
7
lung
7
microvessel
5
disruption
5
pressure aortic
4
failure edema
4
left atrial
4

Similar Publications