GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension.

TitleGIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension.
Publication TypeJournal Article
Year of Publication2021
AuthorsDrzewiecki, K, Choi, J, Brancale, J, Leney-Greene, MA, Sari, S, Dalgiç, B, Aksu, AÜnlüsoy, Şahin, GEvirgen, Ozen, A, Baris, S, Karakoc-Aydiner, E, Jain, D, Kleiner, D, Schmalz, M, Radhakrishnan, K, Zhang, J, Hoebe, K, Su, HC, Pereira, JP, Lenardo, MJ, Lifton, RP, Vilarinho, S
JournalJ Exp Med
Date Published2021 Jul 05

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

Alternate JournalJ Exp Med
PubMed ID33956074
PubMed Central IDPMC8105721
Grant ListK08 DK113109 / DK / NIDDK NIH HHS / United States
P30 DK034989 / DK / NIDDK NIH HHS / United States
T32 GM136651 / GM / NIGMS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States