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1.
Development ; 148(20)2021 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-34550360

RESUMEN

Blood vessel growth and remodelling are essential during embryonic development and disease pathogenesis. The diversity of endothelial cells (ECs) is transcriptionally evident and ECs undergo dynamic changes in gene expression during vessel growth and remodelling. Here, we investigated the role of the histone acetyltransferase HBO1 (KAT7), which is important for activating genes during development and for histone H3 lysine 14 acetylation (H3K14ac). Loss of HBO1 and H3K14ac impaired developmental sprouting angiogenesis and reduced pathological EC overgrowth in the retinal endothelium. Single-cell RNA sequencing of retinal ECs revealed an increased abundance of tip cells in Hbo1-deficient retinas, which led to EC overcrowding in the retinal sprouting front and prevented efficient tip cell migration. We found that H3K14ac was highly abundant in the endothelial genome in both intra- and intergenic regions, suggesting that HBO1 acts as a genome organiser that promotes efficient tip cell behaviour necessary for sprouting angiogenesis. This article has an associated 'The people behind the papers' interview.


Asunto(s)
Histona Acetiltransferasas/metabolismo , Neovascularización Patológica/metabolismo , Acetilación , Animales , Movimiento Celular/fisiología , Células Cultivadas , Desarrollo Embrionario/fisiología , Células Endoteliales/metabolismo , Femenino , Histonas/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Lisina/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
2.
Blood ; 139(6): 845-858, 2022 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-34724565

RESUMEN

The histone acetyltransferase HBO1 (MYST2, KAT7) is indispensable for postgastrulation development, histone H3 lysine 14 acetylation (H3K14Ac), and the expression of embryonic patterning genes. In this study, we report the role of HBO1 in regulating hematopoietic stem cell function in adult hematopoiesis. We used 2 complementary cre-recombinase transgenes to conditionally delete Hbo1 (Mx1-Cre and Rosa26-CreERT2). Hbo1-null mice became moribund due to hematopoietic failure with pancytopenia in the blood and bone marrow 2 to 6 weeks after Hbo1 deletion. Hbo1-deleted bone marrow cells failed to repopulate hemoablated recipients in competitive transplantation experiments. Hbo1 deletion caused a rapid loss of hematopoietic progenitors. The numbers of lineage-restricted progenitors for the erythroid, myeloid, B-, and T-cell lineages were reduced. Loss of HBO1 resulted in an abnormally high rate of recruitment of quiescent hematopoietic stem cells (HSCs) into the cell cycle. Cycling HSCs produced progenitors at the expense of self-renewal, which led to the exhaustion of the HSC pool. Mechanistically, genes important for HSC functions were downregulated in HSC-enriched cell populations after Hbo1 deletion, including genes essential for HSC quiescence and self-renewal, such as Mpl, Tek(Tie-2), Gfi1b, Egr1, Tal1(Scl), Gata2, Erg, Pbx1, Meis1, and Hox9, as well as genes important for multipotent progenitor cells and lineage-specific progenitor cells, such as Gata1. HBO1 was required for H3K14Ac through the genome and particularly at gene loci required for HSC quiescence and self-renewal. Our data indicate that HBO1 promotes the expression of a transcription factor network essential for HSC maintenance and self-renewal in adult hematopoiesis.


Asunto(s)
Autorrenovación de las Células , Células Madre Hematopoyéticas , Histona Acetiltransferasas , Animales , Células Cultivadas , Senescencia Celular , Eliminación de Gen , Hematopoyesis , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Ratones Endogámicos C57BL
3.
Growth Factors ; 37(1-2): 53-67, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-31284789

RESUMEN

Angiogenic blood vessel growth is essential to ensure organs receive adequate blood supply to support normal organ function and homeostasis. Angiogenesis involves a complex series of cellular events through which new vessels grow out from existing vasculature. Growth factor signaling, layered over a range of other signaling inputs, orchestrates this process. The response of endothelial cells (ECs) to growth factor signals must be carefully controlled through feedback mechanisms to prevent excessive vessel growth, remodeling or destabilization. In this article, we summarize recent findings describing how ECs respond to growth factor signals during blood vessel development and homeostasis and how perturbation of these responses can lead to disease.


Asunto(s)
Neovascularización Fisiológica , Transducción de Señal , Enfermedades Vasculares/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Endotelio Vascular/crecimiento & desarrollo , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiología , Humanos , Enfermedades Vasculares/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética
4.
Development ; 143(16): 2973-82, 2016 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-27471260

RESUMEN

The growth of hierarchical blood vessel networks occurs by angiogenesis. During this process, new vessel growth is accompanied by the removal of redundant vessel segments by selective vessel regression ('pruning') and a reduction in endothelial cell (EC) density in order to establish an efficient, hierarchical network. EC apoptosis has long been recognised for its association with angiogenesis, but its contribution to this process has remained unclear. We generated mice in which EC apoptosis was blocked by tissue-specific deletion of the apoptosis effector proteins BAK and BAX. Using the retina as a model, we found that apoptosis made a minor contribution to the efficiency of capillary regression around arteries where apoptosis was most concentrated, but was otherwise dispensable for vessel pruning. Instead, apoptosis was necessary for the removal of non-perfused vessel segments and the reduction in EC density that occurs during vessel maturation. In the absence of apoptosis, increased EC density resulted in an increase in the diameter of capillaries, but not arteries or veins. Our findings show that apoptosis does not influence the number of vessels generated during angiogenesis. Rather it removes non-perfused vessel segments and regulates EC number during vessel maturation, which has vessel-specific consequences for vessel diameter.


Asunto(s)
Apoptosis/fisiología , Endotelio Vascular/citología , Animales , Apoptosis/genética , Células Endoteliales/citología , Células Endoteliales/metabolismo , Masculino , Ratones , Neovascularización Patológica/metabolismo , Neovascularización Patológica/fisiopatología , Retina/citología , Retina/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo
6.
Cell Mol Life Sci ; 74(24): 4387-4403, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28646366

RESUMEN

Blood vessel regression is an essential process for ensuring blood vessel networks function at optimal efficiency and for matching blood supply to the metabolic needs of tissues as they change over time. Angiogenesis is the major mechanism by which new blood vessels are produced, but the vessel growth associated with angiogenesis must be complemented by remodeling and maturation events including the removal of redundant vessel segments and cells to fashion the newly forming vasculature into an efficient, hierarchical network. This review will summarize recent findings on the role that endothelial cell apoptosis plays in vascular remodeling during angiogenesis and in vessel regression more generally.


Asunto(s)
Apoptosis/fisiología , Células Endoteliales/patología , Endotelio Vascular/patología , Neovascularización Patológica/patología , Neovascularización Fisiológica/fisiología , Animales , Humanos
7.
Cell Death Differ ; 30(1): 27-36, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35871233

RESUMEN

Caspase-8 transduces signals from death receptor ligands, such as tumor necrosis factor, to drive potent responses including inflammation, cell proliferation or cell death. This is a developmentally essential function because in utero deletion of endothelial Caspase-8 causes systemic circulatory collapse during embryogenesis. Whether endothelial Caspase-8 is also required for cardiovascular patency during adulthood was unknown. To address this question, we used an inducible Cre recombinase system to delete endothelial Casp8 in 6-week-old conditionally gene-targeted mice. Extensive whole body vascular gene targeting was confirmed, yet the dominant phenotype was fatal hemorrhagic lesions exclusively within the small intestine. The emergence of these intestinal lesions was not a maladaptive immune response to endothelial Caspase-8-deficiency, but instead relied upon aberrant Toll-like receptor sensing of microbial commensals and tumor necrosis factor receptor signaling. This lethal phenotype was prevented in compound mutant mice that lacked the necroptotic cell death effector, MLKL. Thus, distinct from its systemic role during embryogenesis, our data show that dysregulated microbial- and death receptor-signaling uniquely culminate in the adult mouse small intestine to unleash MLKL-dependent necroptotic hemorrhage after loss of endothelial Caspase-8. These data support a critical role for Caspase-8 in preserving gut vascular integrity in the face of microbial commensals.


Asunto(s)
Hemorragia , Inflamación , Ratones , Animales , Caspasa 8/genética , Caspasa 8/metabolismo , Muerte Celular/genética , Inflamación/metabolismo , Receptores de Muerte Celular/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Apoptosis
8.
Methods Mol Biol ; 2441: 29-39, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35099726

RESUMEN

Angiogenic vessel remodeling is a critical step in establishing a hierarchical vessel network. Vessel networks rapidly expand through angiogenesis in response to pro-angiogenic factors. This leads to an initially dense vessel network that requires selective regression of vessel branches to establish a hierarchical conduit for blood flow, a process known as pruning. This involves migration of endothelial cells from low-flow vessels to adjacent high-flow vessels and generally occurs independently of cell death. Vessels may also regress in response to other stimuli, including reduced metabolic demand, redundancy, and pathological stimuli. In these contexts, widespread vessel regression typically occurs and involves loss of endothelial cells by apoptotic cell death. Thus, vessel remodeling occurs via both apoptosis independent and dependent vessel regression. In this chapter, we outline a semi-automated method for quantifying vessel regression using the neonatal model of angiogenesis. We further provide instruction on analyzing endothelial apoptosis in this model.


Asunto(s)
Células Endoteliales , Neovascularización Patológica , Apoptosis/fisiología , Muerte Celular , Células Endoteliales/metabolismo , Humanos , Recién Nacido , Neovascularización Patológica/patología , Neovascularización Fisiológica/fisiología , Remodelación Vascular
9.
Commun Biol ; 4(1): 878, 2021 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-34267311

RESUMEN

Angiogenesis underlies development, physiology and pathogenesis of cancer, eye and cardiovascular diseases. Inhibiting aberrant angiogenesis using anti-angiogenic therapy (AAT) has been successful in the clinical treatment of cancer and eye diseases. However, resistance to AAT inevitably occurs and its molecular basis remains poorly understood. Here, we uncover molecular modifiers of the blood endothelial cell (EC) response to a widely used AAT bevacizumab by performing a pooled genetic screen using three-dimensional microcarrier-based cell culture and CRISPR-Cas9. Functional inhibition of the epigenetic reader BET family of proteins BRD2/3/4 shows unexpected mitigating effects on EC survival and/or proliferation upon VEGFA blockade. Moreover, transcriptomic and pathway analyses reveal an interaction between epigenetic regulation and anti-angiogenesis, which may affect chromosomal structure and activity in ECs via the cell cycle regulator CDC25B phosphatase. Collectively, our findings provide insight into epigenetic regulation of the EC response to VEGFA blockade and may facilitate development of quality biomarkers and strategies for overcoming resistance to AAT.


Asunto(s)
Inhibidores de la Angiogénesis/genética , Bevacizumab/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Epigénesis Genética , Sangre , Células Endoteliales/efectos de los fármacos
10.
J Clin Invest ; 130(8): 4235-4251, 2020 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-32427589

RESUMEN

Aberrant, neovascular retinal blood vessel growth is a vision-threatening complication in ischemic retinal diseases. It is driven by retinal hypoxia frequently caused by capillary nonperfusion and endothelial cell (EC) loss. We investigated the role of EC apoptosis in this process using a mouse model of ischemic retinopathy, in which vessel closure and EC apoptosis cause capillary regression and retinal ischemia followed by neovascularization. Protecting ECs from apoptosis in this model did not prevent capillary closure or retinal ischemia. Nonetheless, it prevented the clearance of ECs from closed capillaries, delaying vessel regression and allowing ECs to persist in clusters throughout the ischemic zone. In response to hypoxia, these preserved ECs underwent a vessel sprouting response and rapidly reassembled into a functional vascular network. This alleviated retinal hypoxia, preventing subsequent pathogenic neovascularization. Vessel reassembly was not limited by VEGFA neutralization, suggesting it was not dependent on the excess VEGFA produced by the ischemic retina. Neutralization of ANG2 did not prevent vessel reassembly, but did impair subsequent angiogenic expansion of the reassembled vessels. Blockade of EC apoptosis may promote ischemic tissue revascularization by preserving ECs within ischemic tissue that retain the capacity to reassemble a functional network and rapidly restore blood supply.


Asunto(s)
Apoptosis , Células Endoteliales/metabolismo , Isquemia/metabolismo , Vasos Retinianos/metabolismo , Ribonucleasa Pancreática/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Modelos Animales de Enfermedad , Células Endoteliales/patología , Isquemia/genética , Isquemia/patología , Ratones , Ratones Noqueados , Enfermedades de la Retina , Vasos Retinianos/patología , Ribonucleasa Pancreática/genética , Factor A de Crecimiento Endotelial Vascular/genética
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