Faculty Collaboration Database

Ciliogenesis mechanisms mediated by PAK2-ARL13B signaling in brain endothelial cells is responsible for vascular stability. Biochem Pharmacol 2022 Aug;202:115143

Date

06/15/2022

Pubmed ID

35700757

DOI

10.1016/j.bcp.2022.115143

Scopus ID

2-s2.0-85132215893 (requires institutional sign-in at Scopus site)   4 Citations

Abstract

In the developing vasculature, cilia, microtubule-based organelles that project from the apical surface of endothelial cells (ECs), have been identified to function cell autonomously to promote vascular integrity and prevent hemorrhage. To date, the underlying mechanisms of endothelial cilia formation (ciliogenesis) are not fully understood. Understanding these mechanisms is likely to open new avenues for targeting EC-cilia to promote vascular stability. Here, we hypothesized that brain ECs ciliogenesis and the underlying mechanisms that control this process are critical for brain vascular stability. To investigate this hypothesis, we utilized multiple approaches including developmental zebrafish model system and primary cell culture systems. In the p21 activated kinase 2 (pak2a) zebrafish vascular stability mutant [redhead (rhd)] that shows cerebral hemorrhage, we observed significant decrease in cilia-inducing protein ADP Ribosylation Factor Like GTPase 13B (Arl13b), and a 4-fold decrease in cilia numbers. Overexpressing ARL13B-GFP fusion mRNA rescues the cilia numbers (1-2-fold) in brain vessels, and the cerebral hemorrhage phenotype. Further, this phenotypic rescue occurs at a critical time in development (24 h post fertilization), prior to initiation of blood flow to the brain vessels. Extensive biochemical mechanistic studies in primary human brain microvascular ECs implicate ligands platelet-derived growth factor-BB (PDGF-BB), and vascular endothelial growth factor-A (VEGF-A) trigger PAK2-ARL13B ciliogenesis and signal through cell surface VEGFR-2 receptor. Thus, collectively, we have implicated a critical brain ECs ciliogenesis signal that converges on PAK2-ARL13B proteins to promote vascular stability.

Author List

Thirugnanam K, Prabhudesai S, Van Why E, Pan A, Gupta A, Foreman K, Zennadi R, Rarick KR, Nauli SM, Palecek SP, Ramchandran R

Authors

Amy Y. Pan PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Ramani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin
Kevin Richard Rarick PhD Assistant Professor in the Pediatrics department at Medical College of Wisconsin
Karthikeyan Thirugnanam PhD Postdoctoral Fellow in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

ADP-Ribosylation Factors
Animals
Brain
Cerebral Hemorrhage
Endothelial Cells
Humans
Vascular Endothelial Growth Factor A
Zebrafish
Zebrafish Proteins
p21-Activated Kinases