Transcriptional Control of Endothelial Cell Development

Cardiovascular Research Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, 94158, USA.
Developmental Cell (Impact Factor: 9.71). 03/2009; 16(2):180-95. DOI: 10.1016/j.devcel.2009.01.014
Source: PubMed


The transcription factors that regulate endothelial cell development have been a focus of active research for several years, and many players in the endothelial transcriptional program have been identified. This review discusses the function of several major regulators of endothelial transcription, including members of the Sox, Ets, Forkhead, GATA, and Kruppel-like families. This review also highlights recent developments aimed at unraveling the combinatorial mechanisms and transcription factor interactions that regulate endothelial cell specification and differentiation during vasculogenesis and angiogenesis.

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    • "Ets-1 belongs to the ets family, which consists of transcription factors involved in vasculo- and angiogenesis [16]. Although we found downregulated Ets-1, Ets-1 null mice are viable, probably due to redundancy among ETS members [16]. Therefore, the mechanism(s) that explain embryonic lethality in the absence of PRKCD and PRKCE cannot be explained through a pathway that only involves ETS-1. "
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    ABSTRACT: Protein Kinase C delta and epsilon are mediators of important cellular events, such as cell proliferation, migration or apoptosis. The formation of blood vessels, i.e., vasculo- and angiogenesis, is a process where these isoforms have also been shown to participate. However, mice deficient in either Protein Kinase C delta or epsilon are viable and therefore their individual contribution to the formation of the vasculature appeared so far dispensable. In this study, we show that double null mutation of Protein Kinase C delta and epsilon causes embryonic lethality at approximately E9.5. At this stage, whole mount staining of the endothelial marker CD31 in double null embryos revealed defective blood vessel formation. Moreover, culture of double deficient mouse allantois showed impaired endothelial cell organization, and analyses of double deficient embryo sections showed dilated vessels, decreased endothelial-specific adherent junctions, and decreased contact of endothelial cells with mural cells. Protein kinase C delta and epsilon also appeared essential for vascular smooth muscle cell differentiation, since α-smooth muscle actin, a classical marker for vascular smooth muscle cells, was almost undetectable in double deficient embryonic aorta at E9.5. Subsequent qPCR analyses showed decreased VE-cadherin, Vegfr2, Cd31, Cdh2, Ets1, and Fli-1, among other angiogenesis related transcripts in double deficient embryos. Taken together, these data suggest for the first time an in vivo redundant role between members of the novel Protein Kinase C subfamily that allows for mutual compensation during mouse embryonic development, with vasculogenesis/angiogenesis as an obvious common function of these two Protein Kinase Cs. Protein Kinase C delta and epsilon might therefore be useful targets for inhibiting vasculo- and/or angiogenesis.
    PLoS ONE 08/2014; 9(8):e103686. DOI:10.1371/journal.pone.0103686 · 3.23 Impact Factor
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    • "Moreover, Pbx1 silencing impairs endothelial cell migration and blocks angiogenesis [61]. Also, in the 3′ UTR of the number of upregulated genes, we observed several binding sites for the Sox family transcription factors important in the development of fetal vasculogenesis [62] and postnatal angiogenesis [63]. Further experiments are needed, however, to establish the role of Pbx1 in the regulation of angiogenesis pathways such as VEGF and PI3/AKT, and their role in LTH acclimatization. "
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    ABSTRACT: In humans and other species, long-term hypoxia (LTH) during pregnancy can lead to intrauterine growth restriction with reduced body/brain weight, dysregulation of cerebral blood flow (CBF), and other problems. To identify the signal transduction pathways and critical molecules, which may be involved in acclimatization to high altitude LTH, we conducted microarray with advanced bioinformatic analysis on carotid arteries (CA) from the normoxic near-term ovine fetus at sea-level and those acclimatized to high altitude for 110+ days during gestation. In response to LTH acclimatization, in fetal CA we identified mRNA from 38 genes upregulated >2 fold (P<0.05) and 9 genes downregulated >2-fold (P<0.05). The major genes with upregulated mRNA were SLC1A3, Insulin-like growth factor (IGF) binding protein 3, IGF type 2 receptor, transforming growth factor (TGF) Beta-3, and genes involved in the AKT and BCL2 signal transduction networks. Most genes with upregulated mRNA have a common motif for Pbx/Knotted homeobox in the promoter region, and Sox family binding sites in the 3' un translated region (UTR). Genes with downregulated mRNA included those involved in the P53 pathway and 5-lipoxygenase activating proteins. The promoter region of all genes with downregulated mRNA, had a common 49 bp region with a binding site for DOT6 and TOD6, components of the RPD3 histone deacetylase complex RPD3C(L). We also identified miRNA complementary to a number of the altered genes. Thus, the present study identified molecules in the ovine fetus, which may play a role in the acclimatization response to high-altitude associated LTH.
    PLoS ONE 12/2013; 8(12):e82200. DOI:10.1371/journal.pone.0082200 · 3.23 Impact Factor
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    • "As the vasculature develops, ECs become differentiated into either arterial or venous specific cells. Notch signaling is crucial during this process, while several transcription factors have been identified that also play a role in this development [118]. Specifically, Notch signaling is important in promoting EC differentiation toward arterial cell differentiation suppressing venous cell development. "
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    ABSTRACT: Endothelial cells (ECs) are a heterogeneous population that fulfills many physiological processes. ECs also actively participate in both innate and adaptive immune responses. ECs are one of the first cell types to detect foreign pathogens and endogenous metabolite-related danger signals in the bloodstream, in which ECs function as danger signal sensors. Treatment with lipopolysaccharide activates ECs, causing the production of pro-inflammatory cytokines and chemokines, which amplify the immune response by recruiting immune cells. Thus, ECs function as immune/inflammation effectors and immune cell mobilizers. ECs also induce cytokine production by immune cells, in which ECs function as immune regulators either by activating or suppressing immune cell function. In addition, under certain conditions, ECs can serve as antigen presenting cells (antigen presenters) by expressing both MHC I and II molecules and presenting endothelial antigens to T cells. These facts along with the new concept of endothelial plasticity suggest that ECs are dynamic cells that respond to extracellular environmental changes and play a meaningful role in immune system function. Based on these novel EC functions, we propose a new paradigm that ECs are conditional innate immune cells. This paradigm provides a novel insight into the functions of ECs in inflammatory/immune pathologies.
    Journal of Hematology & Oncology 08/2013; 6(1):61. DOI:10.1186/1756-8722-6-61 · 4.81 Impact Factor
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