Endothelial phosphoinositide 3-kinase-β inactivation confers protection from immune-mediated vascular injury

Area of Science:

• Immunology
• Vascular Biology
• Molecular Medicine

Background:

• Immune cell-mediated injury of graft vasculature limits heart transplant survival.
• Endothelial cells (ECs) play a critical role in graft rejection and repair.
• The specific role of phosphoinositide 3-kinase-β (PI3Kβ) in ECs during this process is not fully understood.

Purpose of the Study:

• To investigate the role of the PI3Kβ isoform in endothelial cells during immune-mediated coronary vascular injury and repair in a mouse heart transplant model.
• To determine if inhibiting PI3Kβ in ECs can prevent graft vasculopathy.

Main Methods:

• Allogeneic heart transplantation in mice using wild-type, PI3Kβ inhibitor-treated, or endothelial-selective PI3Kβ knockout (ECβKO) grafts.
• Assessment of microvascular EC loss, occlusive vasculopathy, and inflammatory cell infiltration.
• In vitro studies using ECs to analyze the effects of PI3Kβ inhibition on inflammatory molecule expression and signaling pathways (NF-κB).

Main Results:

• ECβKO grafts showed significantly reduced microvascular EC loss and occlusive vasculopathy compared to controls.
• A delay in inflammatory cell infiltration was observed in ECβKO grafts.
• PI3Kβ inhibition or knockout impaired the display of proinflammatory chemokines and adhesion molecules (ICAM1, VCAM1) by ECs.
• PI3Kβ inhibition blocked TNFα-stimulated degradation of IκBα and NF-κB p65 nuclear translocation in ECs.

Conclusions:

• PI3Kβ in endothelial cells is a key mediator of vascular inflammation and injury following heart transplantation.
• Inhibition of PI3Kβ in ECs offers a potential therapeutic strategy to prevent graft vasculopathy and improve transplant outcomes.
• Targeting PI3Kβ may reduce vascular inflammation by modulating EC inflammatory responses and NF-κB signaling.