INVESTIGATING THE ROLE OF PI4KA KINASE IN ANGIOGENESIS

Abstract

Angiogenesis is a multistep process that requires coordinated endothelial cell migration, proliferation, and differentiation. Phosphatidylinositol 4-kinase alpha (PI4KA) generates PI4P at the plasma membrane, which serves as a precursor for key signaling lipids that regulate cytoskeletal organization and cell signaling. However, the specific role of PI4KA in endothelial cell function and angiogenesis remains unclear. In this study, we investigated the role of PI4KA using siRNA-mediated knockdown combined with multiple endothelial functional assays. PI4KA knockdown impaired endothelial tubulogenesis in Matrigel and organotypic co-culture assays, where cells formed flattened and disorganized cords instead of elongated capillary-like structures. In a microfluidic organ-on-chip model, inhibition of PI4KA disrupted sprouting angiogenesis. PI4KA knockdown reduced endothelial cell migration and proliferation. Single-cell morphometric analysis showed that PI4KA-deficient endothelial cells exhibited increased cell size and an increased width-to-length ratio, indicating a less elongated morphology. This was accompanied by reduced actin content and disrupted cytoskeletal organization. PI4KA inhibition reduced intracellular calcium signaling activity and affected the expression of key signaling proteins, including AKT and ERK. These changes were accompanied by increased transendothelial electrical resistance (TEER), indicating enhanced endothelial barrier integrity. Together, our findings demonstrate that PI4KA is a critical regulator of endothelial cell morphology, cytoskeletal organization, and angiogenic function. Loss of PI4KA shifts endothelial cells toward a more stabilized and less angiogenic phenotype, thereby limiting sprouting and vascular network formation. These findings identify PI4KA as a potential therapeutic target for the modulation of pathological angiogenesis.

Date of Award	2026
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences