Shear stress and pathophysiological PI3K involvement in vascular malformations

Area of Science:

• Vascular Biology
• Molecular Genetics
• Cell Signaling

Background:

• Gain-of-function (GOF) mutations in PIK3CA are identified in endothelial cells (ECs) of vascular anomalies.
• PIK3CA mutations are implicated in solid cancers and a spectrum of vascular malformations known as PIKopathies.
• Fluid shear stress (FSS), a physiological stimulus from blood/lymph flow, influences PIKopathy development.

Purpose of the Study:

• To review the role of PIK3CA in mediating EC responses to FSS.
• To discuss PIK3CA dysregulation in vascular anomalies, particularly in low-perfused vasculature.
• To explore therapeutic strategies targeting PI3K signaling in vascular diseases.

Main Methods:

• Literature review focusing on PIK3CA mutations and vascular anomalies.
• Analysis of studies investigating the impact of FSS on ECs with PIK3CA mutations.
• Synthesis of current understanding of PI3K signaling in various vascular disorders.

Main Results:

• PI3K signaling is implicated in EC responses to FSS in lymphatic and capillary beds.
• Increased PI3K signaling contributes to cerebral cavernous malformations in low-perfused brain capillaries.
• Novel findings link PI3K signaling to fast-flow arteriovenous malformations in hereditary hemorrhagic telangiectasias.

Conclusions:

• Understanding PIK3CA's role in FSS response is crucial for developing targeted therapies for PIKopathies.
• PI3K signaling is a critical mediator in diverse vascular anomalies, from simple malformations to complex overgrowth syndromes.
• Targeting GOF PI3K activity offers potential therapeutic avenues for normalizing EC function in diseased vasculature.