Faculty Collaboration Database

Endothelial-specific ablation of serum response factor causes hemorrhaging, yolk sac vascular failure, and embryonic lethality. BMC Dev Biol 2008 Jun 20;8:65

Date

06/24/2008

Pubmed ID

18570667

Pubmed Central ID

PMC2442838

DOI

10.1186/1471-213X-8-65

Scopus ID

2-s2.0-46449109730 (requires institutional sign-in at Scopus site)   17 Citations

Abstract

BACKGROUND: Serum response factor (SRF), a member of the MADS box family of nuclear transcription factors, plays an important role in cardiovascular development and function. Numerous studies demonstrate a central role for SRF in regulating smooth and cardiac muscle cell gene expression. Consistent with this, loss of SRF function blocks differentiation of coronary vascular smooth muscle cells from proepicardial precursors, indicating SRF is necessary for coronary vasculogenesis. The role of SRF in endothelial cell contribution during early vascular development, however, has not been addressed. To investigate this, we generated transgenic mice lacking expression of SRF in endothelial cells. Mice expressing Cre recombinase (Tie2Cre+) under Tie2 promoter control were bred to mice homozygous for Srf alleles containing loxP recombination sites within the Srf gene (Srff/f). Tie2 is a tyrosine kinase receptor expressed predominantly on endothelial cells that mediates signalling during different stages of blood vessel remodelling. Resulting embryos were harvested at specific ages for observation of physical condition and analysis of genotype.

RESULTS: Tie2Cre+/-Srff/f embryos appeared to develop normally compared to wild-type littermates until embryonic day 10.5 (E10.5). Beginning at E11.5, Tie2Cre+/-Srff/f embryos exhibited cerebrovascular hemorrhaging and severely disrupted vascular networks within the yolk sac. Hemorrhaging in mutant embryos became more generalized with age, and by E14.5, most Tie2Cre+/-Srff/f embryos observed were nonviable and grossly necrotic. Hearts of mutant embryos were smaller relative to overall body weight compared to wild-type littermates. Immunohistochemical analysis revealed the presence of vascular endothelial cells; however, vessels failed to undergo appropriate remodelling. Initial analysis by electron microscopy suggested a lack of appropriate cell-cell contacts between endothelial cells. Consistent with this, disrupted E-cadherin staining patterns were observed in mutant embryos.

CONCLUSION: These results provide the first in vivo evidence in support of a role for SRF in endothelial cell function and strongly suggest SRF is required for appropriate vascular remodelling.

Author List

Holtz ML, Misra RP

Author

Ravindra P. Misra PhD Associate Provost, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Embryo, Mammalian
Endothelial Cells
Endothelium, Vascular
Genes, Lethal
Genotype
Hemorrhage
Mice
Mice, Transgenic
Serum Response Factor
Signal Transduction
Transcription Factors
Yolk Sac