GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension

Kaela Drzewiecki, Jungmin Choi, Joseph Brancale, Michael A. Leney-Greene, Sinan Sari, Buket Dalgiç, Aysel Ünlüsoy Aksu, Gülseren Evirgen Şahin, Ahmet Ozen, Safa Baris, Elif Karakoc-Aydiner, Dhanpat Jain, David Kleiner, Michael Schmalz, Kadakkal Radhakrishnan, Junhui Zhang, Kasper Hoebe, Helen C. Su, João P. Pereira, Michael J. LenardoRichard P. Lifton, Sílvia Vilarinho

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbere20201745
JournalJournal of Experimental Medicine
Volume218
Issue number7
DOIs
Publication statusPublished - 2021 May 6

ASJC Scopus subject areas

  • Medicine(all)

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