A novel inducible von Willebrand Factor Cre recombinase mouse strain to study microvascular endothelial cell-specific biological processes in vivo

Dinesh Yadav; Jeremy A Conner; Yimin Wang; Thomas L Saunders; Eroboghene E Ubogu

doi:10.1016/j.vph.2024.107369

A novel inducible von Willebrand Factor Cre recombinase mouse strain to study microvascular endothelial cell-specific biological processes in vivo

Vascul Pharmacol. 2024 Mar 29:155:107369. doi: 10.1016/j.vph.2024.107369. Online ahead of print.

Authors

Dinesh Yadav¹, Jeremy A Conner¹, Yimin Wang¹, Thomas L Saunders², Eroboghene E Ubogu³

Affiliations

¹ Neuromuscular Immunopathology Research Laboratory, Division of Neuromuscular Disease, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.
² Transgenic Animal Model Core, University of Michigan, Ann Arbor, MI, USA.
³ Neuromuscular Immunopathology Research Laboratory, Division of Neuromuscular Disease, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: ubogu@uab.edu.

PMID: 38554988
DOI: 10.1016/j.vph.2024.107369

Abstract

Mouse models are invaluable to understanding fundamental mechanisms in vascular biology during development, in health and different disease states. Several constitutive or inducible models that selectively knockout or knock in genes in vascular endothelial cells exist; however, functional and phenotypic differences exist between microvascular and macrovascular endothelial cells in different organs. In order to study microvascular endothelial cell-specific biological processes, we developed a Tamoxifen-inducible von Willebrand Factor (vWF) Cre recombinase mouse in the SJL background. The transgene consists of the human vWF promoter with the microvascular endothelial cell-selective 734 base pair sequence to drive Cre recombinase fused to a mutant estrogen ligand-binding domain [ERT2] that requires Tamoxifen for activity (CreERT2) followed by a polyadenylation (polyA) signal. We initially observed Tamoxifen-inducible restricted bone marrow megakaryocyte and sciatic nerve microvascular endothelial cell Cre recombinase expression in offspring of a mixed strain hemizygous C57BL/6-SJL founder mouse bred with mT/mG mice, with >90% bone marrow megakaryocyte expression efficiency. Founder mouse offspring were backcrossed to the SJL background by speed congenics, and intercrossed for >10 generations to develop hemizygous Tamoxifen-inducible vWF Cre recombinase (vWF-iCre/+) SJL mice with stable transgene insertion in chromosome 1. Microvascular endothelial cell-specific Cre recombinase expression occurred in the sciatic nerves, brains, spleens, kidneys and gastrocnemius muscles of adult vWF-iCre/+ SJL mice bred with Ai14 mice, with retained low level bone marrow and splenic megakaryocyte expression. This novel mouse strain would support hypothesis-driven mechanistic studies to decipher the role(s) of specific genes transcribed by microvascular endothelial cells during development, as well as in physiologic and pathophysiologic states in an organ- and time-dependent manner.

Keywords: Cre recombinase; Inducible; Mice; Microvascular endothelial cells; Reporter mouse; Sciatic nerves; Tamoxifen; Transgenic mice; Vascular biology; von Willebrand factor.