Open AccessGIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension
Author(s) -
Kaela Drzewiecki,
Jungmin Choi,
Joseph Brancale,
Michael Leney-Greene,
Sinan Sarı,
Buket Dalgıç,
Aysel Ünlüsoy Aksu,
Gülseren Evirgen Şahin,
Ahmet Özen,
Safa Barış,
Elif Karakoç-Aydıner,
Dhanpat Jain,
David E. Kleiner,
Michael J. Schmalz,
Kadakkal Radhakrishnan,
Junhui Zhang,
Kasper Hoebe,
Helen C. Su,
João P. Pereira,
Michael J. Lenardo,
Richard P. Lifton,
Sílvia Vilarinho
Publication year - 2021
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20201745
Subject(s) - portal hypertension , endothelial stem cell , biology , homeostasis , liver disease , endothelial dysfunction , kupffer cell , cirrhosis , medicine , endocrinology , immunology , cancer research , in vitro , biochemistry
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.