Dataset Information

Dosage-dependent requirement for mouse Vezf1 in vascular system development.

ABSTRACT: Vezf1 is an early development gene that encodes a zinc finger transcription factor. In the developing embryo, Vezf1 is expressed in the yolk sac mesoderm and the endothelium of the developing vasculature and, in addition, in mesodermal and neuronal tissues. Targeted inactivation of Vezf1 in mice reveals that it acts in a closely regulated, dose-dependent fashion on the development of the blood vascular and lymphatic system. Homozygous mutant embryos display vascular remodeling defects and loss of vascular integrity leading to localized hemorrhaging. Ultrastructural analysis shows defective endothelial cell adhesion and tight junction formation in the mutant vessels. Moreover, in heterozygous embryos, haploinsufficiency is observed that is characterized by lymphatic hypervascularization associated with hemorrhaging and edema in the jugular region; a phenotype reminiscent of the human congenital lymphatic malformation syndrome cystic hygroma.

SUBMITTER: Kuhnert F

PROVIDER: S-EPMC1453095 | biostudies-literature | 2005 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dosage-dependent requirement for mouse Vezf1 in vascular system development.

Kuhnert Frank F Campagnolo Luisa L Xiong Jing-Wei JW Lemons Derek D Fitch Michael J MJ Zou Zhongmin Z Kiosses William B WB Gardner Humphrey H Stuhlmann Heidi H

Developmental biology 20050701 1

Vezf1 is an early development gene that encodes a zinc finger transcription factor. In the developing embryo, Vezf1 is expressed in the yolk sac mesoderm and the endothelium of the developing vasculature and, in addition, in mesodermal and neuronal tissues. Targeted inactivation of Vezf1 in mice reveals that it acts in a closely regulated, dose-dependent fashion on the development of the blood vascular and lymphatic system. Homozygous mutant embryos display vascular remodeling defects and loss o ...[more]

PMID: 15882861

Similar Datasets

Project description:Purpose: The purpose of this study was 1) to predict the requisite vancomycin daily dose (D van ) used in the target patients suffering from both bacterial infection and hematological malignancies and 2) to construct a vancomycin-dose-graphical tool to assist clinicians to develop vancomycin dosing regimens and further 3) to establish a programming process for vancomycin dynamic dosage adjustment to help clinicians to adjust vancomycin dosing regimens according to physiological and pathogenic factors of the target patients. Methods: The D van model associated with microbial susceptibility, vancomycin pharmacokinetics, and dosing parameters was established, and the D van was estimated based on the established D van model and using Monte Carlo simulations. D van achieving 90% of probability of target attainment (PTA) for bacterial isolate or cumulative fractions of response (CFR) for the bacterial population at a ratio of daily area under the curve (AUC24) to the minimum inhibitory concentration (MIC) [i.e., AUC24/MIC] of 400-600 was considered sufficient to treat infection occurring in the target patients. On the basis of the predicted D van , the physiological states of patients, and the pathogenic variables of infection, a vancomycin-dose-graphical tool for the target patients and a programming process for vancomycin dynamic dosage adjustment were constructed. Results: This study predicted the requisite D van used in patients suffering from both bacterial infection and hematological malignancies and constructed a vancomycin-dose-graphical tool for the target patients, at different physiological states and pathogenic variables, to formulate vancomycin dosing regimens. Also, this study established and expounded the formulation process of vancomycin dosage dynamic adjustment according to fluctuant renal function of the target patients. Conclusion: With the tools, the required D van or vancomycin dosing regimens for the target patients, at different physiological states and pathogenic variables, can be readily known, whether or not vancomycin dynamic dosage adjustment is required.

Project description:Smad4 is a central mediator of transforming growth factor-?/bone morphogenetic protein signaling that controls numerous developmental processes as well as homeostasis in the adult. The present studies sought to understand the function of Smad4 expressed in vascular smooth muscle cells (VSMC) in vascular development and the underlying mechanisms.Breeding of Smad4(flox/flox) mice with SM22?-Cre mice resulted in no viable offspring with SM22?-Cre;Smad4(flox/flox) genotype in a total of 165 newborns. Subsequent characterization of 301 embryos between embryonic day (E) 9.5 and E14.5 demonstrated that mice with SM22?-Cre;Smad4(flox/flox) genotype died between E12.5 and E14.5 because of decreased cell proliferation and increased apoptosis in the embryonic heart and arteries. Additionally, deletion of Smad4 more specifically in SMC with the inducible smooth muscle myosin heavy chain (SMMHC)-Cre mice, in which decreased cell proliferation was observed only in the artery but not the heart, also caused lethality of the knockout embryos at E12.5 and E14.5. The Smad4-deficient VSMC lacked smooth muscle ?-actin filaments, decreased expression of SMC-specific gene markers, and markedly reduced cell proliferation, migration, and attachment. Using specific pharmacological inhibitors and small interfering RNAs, we demonstrated that inhibition of transforming growth factor-? signaling and its regulatory Smad 2/3 decreased VSMC proliferation, migration, and expression of SMC-specific gene markers, whereas inhibition of bone morphogenetic protein signaling only affected VSMC migration.SMC-specific deletion of Smad4 results in vascular defects that lead to embryonic lethality in mice, which may be attributed to decreased VSMC differentiation, proliferation, migration, as well as cell attachment and spreading. The transforming growth factor-? signaling pathway contributes to VSMC differentiation and function, whereas the bone morphogenetic protein signaling pathway regulates VSMC migration. These studies provide important insight into the role of Smad4 and its upstream Smads in regulating SMC function and vascular development of mice.

Dataset Information

Dosage-dependent requirement for mouse Vezf1 in vascular system development.

Publications

Dosage-dependent requirement for mouse Vezf1 in vascular system development.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets