Perivascular matrix densification dysregulates angiogenesis and activates pro-inflammatory endothelial cells

Area of Science:

• Fibrosis research
• Endothelial cell biology
• Wound healing mechanisms

Background:

• Fibrosis contributes to 45% of deaths, impacting organs like lungs, liver, and heart.
• Endothelial cells (ECs) and angiogenesis are implicated in fibrosis, but their precise role remains unclear.
• Understanding EC phenotype in tissue healing versus fibrosis is critical.

Purpose of the Study:

• To investigate the role of endothelial cells (ECs) in fibrotic progression.
• To elucidate the mechanisms by which ECs contribute to fibrosis.
• To identify potential therapeutic targets for anti-fibrotic therapies.

Main Methods:

• Murine lung injury model with EC lineage tracing.
• Microphysiological system (MPS) modeling microvessels in fibrotic matrix.
• Analysis of EC activation, endothelial-to-mesenchymal transition (EndMT), and ATEC phenotypes.

Main Results:

• Aberrant ECs invade fibrotic lung tissue, associated with matrix densification.
• Increased matrix density activates ECs, induces EndMT, and promotes ATEC invasion.
• ATECs exhibit a pro-inflammatory phenotype, secreting TGF-β2 via a VE-cadherin-TGF-βR2 axis.

Conclusions:

• Fibrous matrix destabilizes endothelial adherens junctions, promoting ATEC formation.
• ECs play a significant, previously unrecognized role in fibrotic progression.
• Targeting EC behavior and the VE-cadherin-TGF-βR2 axis may yield novel anti-fibrotic therapies.