A5057642594- Angiogenesis and VEGF in Cancer
- Vascular Malformations Diagnosis and Treatment
- Moyamoya disease diagnosis and treatment
- Axon Guidance and Neuronal Signaling
- Intracranial Aneurysms: Treatment and Complications
- Vascular Anomalies and Treatments
- Intracerebral and Subarachnoid Hemorrhage Research
- Cell Adhesion Molecules Research
- Zebrafish Biomedical Research Applications
- Developmental Biology and Gene Regulation
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Pain Mechanisms and Treatments
- Tracheal and airway disorders
- Epigenetics and DNA Methylation
- Congenital heart defects research
- Hippo pathway signaling and YAP/TAZ
- Mesenchymal stem cell research
- Advanced Fluorescence Microscopy Techniques
- Liver Disease and Transplantation
- Cerebrovascular and genetic disorders
- Hedgehog Signaling Pathway Studies
- Cancer Cells and Metastasis
- Muscle Physiology and Disorders
- Nitric Oxide and Endothelin Effects
- Phagocytosis and Immune Regulation
University of California, San Francisco
2012-2024
University of San Francisco
2024
Massachusetts Institute of Technology
2015
Pulmonary Vascular Research Institute
2008-2009
Iowa State University
1994-1995
Making Split Decisions Development of the vertebrate vasculature has been thought to involve just two mechanisms blood vessel formation. Herbert et al. (p. 294 ; see Perspective by Benedito and Adams ) identified a third mechanism in zebrafish which distinct, unconnected vessels can be derived from single precursor vessel. Several vascular endothelial growth factors signaling pathways, including ephrin notch signaling, coordinated sorting segregation mixture arterial venous-fated cells into...
β1 integrin (encoded by Itgb1) is established as a regulator of angiogenesis based upon the phenotypes complete knockouts heterodimer partners or ligands and antibody inhibition studies in mice. Its direct function endothelial cells (ECs) vivo has not been determined because Itgb1-/- embryos die before vascular development. Excision Itgb1 from ECs subset hematopoietic cells, using Tie2-Cre, resulted abnormal development embryonic day(e) 8.5 lethality e10.5. Tie1-Cre mediated more restricted...
Background The ability to measure blood velocities is critical for studying vascular development, physiology, and pathology. A key challenge quantify a wide range of in vessels deep within living specimens with concurrent diffraction-limited resolution imaging cells. Two-photon laser scanning microscopy (TPLSM) has shown tremendous promise analyzing hundreds micrometers animals cellular resolution. However, current analysis TPLSM-based data limited the lower not adequate study faster many...
Significance Brain arteriovenous malformations are focal lesions of enlarged, tangled vessels that shunt blood from arteries directly to veins. They can cause ischemia, hemorrhage, disability, and death, particularly in young people, accounting for 50% childhood stroke. The molecular etiology the disease remains poorly understood, hindering development therapeutic treatments. Here, we report that, an animal model, lesion arises enlargement capillary-like vessels. Notch signaling endothelium...
Monitoring of cell-cell communication in multicellular organisms is fundamental to understanding diverse biological processes such as embryogenesis and tumorigenesis. To track contacts vivo, we developed an intercellular genetic technology monitor contact trace cell histories by permanently marking between cells. In mice, engineered artificial Notch ligand into one (the sender cell) receptor another receiver cell). Contact the cells triggered a synthetic signaling that activated downstream...
Brain arteriovenous malformations (BAVMs) can cause devastating stroke in young people and contribute to half of all hemorrhagic children. Unfortunately, the pathogenesis BAVMs is unknown. In this article we show that activation Notch signaling endothelium during brain development causes BAVM mice. We turned on constitutively active Notch4 ( int3 ) expression endothelial cells from birth by using tetracycline-regulatable system. All mutants developed hallmarks BAVMs, including cerebral...
A mutual coordination of size between developing arteries and veins is essential for establishing proper connections these vessels and, ultimately, a functional vasculature; however, the cellular molecular regulation this parity not understood. Here, we demonstrate that dorsal aorta cardinal vein reciprocally balanced. Mouse embryos carrying gain-of-function Notch alleles show enlarged aortae underdeveloped veins, whereas those with loss-of-function mutations small large veins. does affect...
The c-Myc protein has been implicated in playing a pivotal role regulating the expression of large number genes involved many aspects cellular function. Consistent with this view, embryos lacking c-myc gene exhibit severe developmental defects and die before midgestation. Here, we show that Sox2Cre-mediated deletion conditional c-myc(flox) allele specifically epiblast (hence trophoectoderm primitive endoderm structures are wild type) rescues majority abnormalities previously characterized...
Abnormally enlarged blood vessels underlie many life-threatening disorders including arteriovenous (AV) malformations (AVMs). The core defect in AVMs is high-flow AV shunts, which connect arteries directly to veins, "stealing" from capillaries. Here, we studied mouse brain shunts caused by up-regulation of Notch signaling endothelial cells (ECs) through transgenic expression constitutively active Notch4 (Notch4*). Using four-dimensional two-photon imaging a cranial window, found that...
The c-myc proto-oncogene, which is crucial for the progression of many human cancers, has been implicated in key cellular processes diverse cell types, including endothelial cells that line blood vessels and are critical angiogenesis. de novo differentiation known as vasculogenesis, whereas growth new from pre-existing To ascertain function vascular development, we deleted selected lineages. Embryos lacking hematopoietic lineages phenocopied those entire embryo proper. At embryonic day (E)...
Coordinated arterial-venous differentiation is crucial for vascular development and function. The origin of the cardinal vein (CV) in mammals unknown, while conflicting theories have been reported chick zebrafish. Here, we provide first molecular characterization endothelial cells (ECs) expressing venous markers, or venous-fated ECs, within emergent dorsal aorta (DA). These markers Coup-TFII EphB4, cohabited early DA with ECs arterial ephrin B2, Notch connexin 40. mixed expressed either...
Liver vasculature is crucial for adequate hepatic functions. Global deletion of Notch signaling in mice results liver vascular pathologies. However, whether endothelium essential structure and function remains unknown. To uncover the endothelial liver, we deleted Rbpj, a transcription factor mediating all canonical signaling, or Notch1 from postnatal mice. We investigated defects these mutants. The was severely affected within 2 weeks Rbpj birth. Two‐week old mutant had enlarged vessels on...
Arteriovenous malformations (AVMs) are tortuous vessels characterized by arteriovenous (AV) shunts, which displace capillaries and shunt blood directly from artery to vein. Notch signaling regulates embryonic AV specification promoting arterial, as opposed venous, endothelial cell (EC) fate. To understand the essential role of in postnatal organization, we used inducible Cre-loxP recombination delete Rbpj, a mediator canonical signaling, ECs mice. Deletion Rbpj birth resulted features AVMs...
The bone morphogenetic protein (BMP) pathway is known to be involved in limb myogenesis during development, but whether it postnatal muscle regeneration unclear. We have found that adult inhibitor of differentiation (Id)-mutant (Id1(+/-)Id3(-/-)) mice display delayed and reduced skeletal after injury compared with either wild-type littermates or Id3-null mice. Immunoblotting lysates revealed that, not only were Id1 Id3 highly upregulated within 24 h injury, other upstream components the BMP...
Lung arteriovenous (AV) shunts or malformations cause significant morbidity and mortality in several distinct clinical syndromes. For most patients with lung AV shunts, there is still no optimal treatment. The underlying molecular cellular etiology for remains elusive, currently described animal models have insufficiently addressed this problem. Using a tetracycline-repressible system, we expressed constitutively active Notch4 (Notch4*) specifically the endothelium of adult mice. More than...
The functions of blood flow in the morphogenesis mammalian arteries and veins are not well understood. We examined development dorsal aorta (DA) cardinal vein (CV) Ncx1 -/- mutants, which lack due to a deficiency sodium calcium ion exchanger expressed specifically heart. mutant DA CV were abnormally connected. endothelium lacked normal expression arterial markers ephrin-B2 Connexin-40. Notch1 activation, known promote specification, was decreased endothelial cells (ECs), ectopically venous...
Mechanisms underlying arteriovenous malformations (AVMs) are poorly understood. Using mice with endothelial cell (EC) expression of constitutively active Notch4 (Notch4* EC ), we show decreased arteriolar tone in vivo during brain AVM initiation. Reduced vascular is a primary effect Notch4* , as isolated pial arteries from asymptomatic exhibited reduced pressure-induced arterial ex vivo. The nitric oxide (NO) synthase (NOS) inhibitor NG-nitro- l -arginine (L-NNA) corrected defects both...
Upregulation of Notch signaling is associated with brain arteriovenous malformation (bAVM), a disease that lacks pharmacological treatments. Tetracycline (tet)-regulatable endothelial expression constitutively active Notch4 (Notch4*tetEC) from birth induced bAVMs in 100% mice by P16. To test whether targeting downstream signaling, while sustaining the causal Notch4*tetEC expression, induces AVM normalization, we deleted Rbpj, mediator endothelium P16, combining tet-repressible...
The cell surface protein ephrin-B2 is expressed in arterial and not venous ECs throughout development adulthood. Endothelial required for vascular angiogenesis, but its role established arteries currently unknown. We investigated the physiological of signaling adult endothelium.We generated conditional knockout mice lacking Efnb2 gene specifically evaluated vasodilation responses to blood flow increase ACh cremaster muscle preparation by intravital microscope carotid artery vivo...