Vascular Endothelial Growth Factor-B–Deficient Mice Display an Atrial Conduction Defect

Aase, Karin; Euler, Gabriel von; Li, Xuri; Pontén, Annica; Thorén, Peter; Cao, Renhai; Cao, Yihai; Olofsson, Birgitta; Gebré-Medhin, Samuel; Pekny, Milos; Alitalo, Kari; Betsholtz, Christer; Eriksson, Ulf

doi:10.1161/01.cir.104.3.358

Cited by 148 publications

(128 citation statements)

References 32 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…Similarly, no vascular abnormalities were detected at other stages of Vegfb-deficient mice compared with wild-type stage-matched controls. These findings show that deletion of the Vegfb gene in mice does not affect vascular development in the brain, eye, and peripheral tissues, which are consistent with previous reports (18,19,22). Thus, there are major functional differences of VEGF-B in zebrafish and mice.…”

Section: Resultssupporting

confidence: 92%

“…One of our surprising findings is that VEGF-B is expressed at extremely high levels in the brain of developing embryos. VEGF-B, as a VEGFR1-binding ligand, lacks obvious biological functions in mouse-based experimental models (18,19,22). Genetic deletion of the Vegfb gene in mice does not result in any obvious vascular phenotype, and Vegfb-null mice develop normally.…”

Section: Discussionmentioning

confidence: 99%

“…These findings demonstrate that an optimal level of VEGF-A expression is needed for embryonic development. Unlike VEGF-A, deletion of the Vegfb gene in mice does not produce an overt phenotype, except slight cardiovascular impairments (18,19). Recently, it has been found that VEGF-B-deficient animals exhibit defective lipid uptake in endothelial cells (20,21).…”

mentioning

confidence: 99%

See 2 more Smart Citations

VEGF-B-Neuropilin-1 signaling is spatiotemporally indispensable for vascular and neuronal development in zebrafish

Jensen

Nakamura

Bräutigam

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Physiological functions of vascular endothelial growth factor (VEGF)-B remain an enigma, and deletion of the Vegfb gene in mice lacks an overt phenotype. Here we show that knockdown of Vegfba, but not Vegfbb, in zebrafish embryos by specific morpholinos produced a lethal phenotype owing to vascular and neuronal defects in the brain. Vegfba morpholinos also markedly prevented development of hyaloid vasculatures in the retina, but had little effects on peripheral vascular development. Consistent with phenotypic defects, Vegfba, but not Vegfaa, mRNA was primarily expressed in the brain of developing zebrafish embryos. Interestingly, in situ detection of Neuropilin1 (Nrp1) mRNA showed an overlapping expression pattern with Vegfba, and knockdown of Nrp1 produced a nearly identically lethal phenotype as Vegfba knockdown. Furthermore, zebrafish VEGF-Ba protein directly bound to NRP1. Importantly, gain-of-function by exogenous delivery of mRNAs coding for NRP1-binding ligands VEGF-B or VEGF-A to the zebrafish embryos rescued the lethal phenotype by normalizing vascular development. Similarly, exposure of zebrafish embryos to hypoxia also rescued the Vegfba morpholino-induced vascular defects in the brain by increasing VEGF-A expression. Independent evidence of VEGF-A gain-of-function was provided by using a functionally defective Vhl-mutant zebrafish strain, which again rescued the Vegfba morpholino-induced vascular defects. These findings show that VEGF-B is spatiotemporally required for vascular development in zebrafish embryos and that NRP1, but not VEGFR1, mediates the essential signaling.

show abstract

Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

VEGF-B-Neuropilin-1 signaling is spatiotemporally indispensable for vascular and neuronal development in zebrafish

Jensen

Nakamura

Bräutigam

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Consistent with the receptor binding patterns, PlGF and VEGF-B do not seem to display significant physiological functions. For example, plgf or vegf-b-null mice develop normally and lack obvious vascular and non-vascular defects during the adulthood (29,30). However, recent studies show that PlGF might significantly contribute to pathological angiogenesis such as tumor neovascularization, vascular regeneration under tissue ischemia, and wound healing (31)(32)(33)(34).…”

mentioning

confidence: 99%

Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature

Hedlund

Hosaka

Zhong

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Vascular functions of PlGF remain poorly understood and controversial. Here, we show that tumor cell-derived PlGF-1 and PlGF-2 displayed significant remodeling effects on the tumor vasculature, leading to a normalized vascular phenotype and improved functions against leakage. In two murine tumor models, that is, T241 fibrosarcoma and Lewis lung carcinoma, stable expression of PlGF-1 and PlGF-2 in tumor cells resulted in significant reduction of tumor microvascular density and branch formation. Markedly, the vasculature in PlGF-expressing tumors consisted of relatively large-diameter microvessels with substantial improvement of pericyte coverage. Similarly, PlGF-induced vascular normalization and remodeling were also observed in a spontaneous human choriocarcinoma that expressed endogenous PlGF. Our findings shed light on functions of PlGF as a vascular remodeling factor that normalizes the tumor vasculature and thus may have conceptual implications of cancer therapy. vascular permeability ͉ vascular remodeling

show abstract

“…Mice lacking VEGF-B displayed mild cardiac phenotypes, such as the slightly smaller heart and dysfunctional coronary vasculature in Bellomo VEGF-B −/− mice 67 and a prolonged PQ interval in Aase VEGF-B −/− mice. 71 Though minor phenotype differs, these inferred a protective role of VEGF-B in the normal or ischemic heart. Additional, individuals with diabetes are prone to suffer from CVD.…”

Section: Introductionmentioning

confidence: 99%

Vascular endothelial growth factor-B: Impact on physiology and pathology

Zhu

Gao

et al. 2017

Cell Adhesion & Migration

View full text Add to dashboard Cite

Angiogenesis plays an important role in controlling tissue development and maintaining normal tissue function. Dysregulated angiogenesis is implicated in the pathogenesis of a variety of diseases, particularly diabetes, cancers, and neurodegenerative disorders. As the major regulator of angiogenesis, the vascular endothelial growth factor (VEGF) family is composed of a group of crucial members including VEGF-B. While the physiological roles of VEGF-B remain debatable, increasing evidence suggests that this protein is able to protect certain type of cells from apoptosis under pathological conditions. More importantly, recent studies reveal that VEGF-B is involved in lipid transport and energy metabolism, implicating this protein in obesity, diabetes and related metabolic complications. This article summarizes the current knowledge and understanding of VEGF-B in physiology and pathology, and shed light on the therapeutic potential of this crucial protein.

show abstract

Vascular Endothelial Growth Factor-B–Deficient Mice Display an Atrial Conduction Defect

Abstract: VEGF-B seems to be required for normal heart function in adult animals but is not required for proper development of the cardiovascular system either during development or for angiogenesis in adults.

Cited by 148 publications

References 32 publications

VEGF-B-Neuropilin-1 signaling is spatiotemporally indispensable for vascular and neuronal development in zebrafish

VEGF-B-Neuropilin-1 signaling is spatiotemporally indispensable for vascular and neuronal development in zebrafish

Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature

Vascular endothelial growth factor-B: Impact on physiology and pathology

Contact Info

Product

Resources

About