TY - JOUR
T1 - GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension
AU - Drzewiecki, Kaela
AU - Choi, Jungmin
AU - Brancale, Joseph
AU - Leney-Greene, Michael A.
AU - Sari, Sinan
AU - Dalgiç, Buket
AU - Aksu, Aysel Ünlüsoy
AU - Şahin, Gülseren Evirgen
AU - Ozen, Ahmet
AU - Baris, Safa
AU - Karakoc-Aydiner, Elif
AU - Jain, Dhanpat
AU - Kleiner, David
AU - Schmalz, Michael
AU - Radhakrishnan, Kadakkal
AU - Zhang, Junhui
AU - Hoebe, Kasper
AU - Su, Helen C.
AU - Pereira, João P.
AU - Lenardo, Michael J.
AU - Lifton, Richard P.
AU - Vilarinho, Sílvia
N1 - Funding Information:
of the National Institutes of Health under award K08 DK113109 (to S. Vilarinho); the Yale Liver Center (P30 DK034989); and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. J. Brancale is supported by the National Institute of General Medical Sciences of the National Institutes of Health under award 1T32GM136651-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
This work was in part supported by the National Institutes of Health Centers for Mendelian Genomics (U54 HG006504); the National Institute of Diabetes and Digestive and Kidney Diseases
Publisher Copyright:
© 2021 Drzewiecki et al.
PY - 2021/5/6
Y1 - 2021/5/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105540276&partnerID=8YFLogxK
U2 - 10.1084/jem.20201745
DO - 10.1084/jem.20201745
M3 - Article
C2 - 33956074
AN - SCOPUS:85105540276
SN - 0022-1007
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
M1 - e20201745
ER -