Publications (18)126.85 Total impact
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Article: Elevated vascular endothelial growth factor receptor-2 abundance contributes to increased angiogenesis in vascular endothelial growth factor receptor-1-deficient mice.
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ABSTRACT: Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1) is a potential therapeutic target for cardiovascular diseases, but its role in angiogenesis remains controversial. Whereas germline Vegfr-1(-/-) embryos die of abnormal vascular development in association with excessive endothelial differentiation, mice lacking only the kinase domain appear healthy. We performed Cre-loxP-mediated knockout to abrogate the expression of all known VEGFR-1 functional domains in neonatal and adult mice and analyzed developmental, pathophysiological, and molecular consequences. VEGFR-1 deficiency promoted tip cell formation and endothelial cell proliferation and facilitated angiogenesis of blood vessels that matured and perfused properly. Vascular permeability was normal at the basal level but elevated in response to high doses of exogenous VEGF-A. In the postinfarct ischemic cardiomyopathy model, VEGFR-1 deficiency supported robust angiogenesis and protected against myocardial infarction. VEGFR-1 knockout led to abundant accumulation of VEGFR-2 at the protein level, increased VEGFR-2 tyrosine phosphorylation transiently, and enhanced serine phosphorylation of Akt and ERK. Interestingly, increased angiogenesis, tip cell formation, vascular permeability, VEGFR-2 accumulation, and Akt phosphorylation could be partially rescued or suppressed by one or more of the following manipulations, including injection of the VEGFR-2 selective inhibitor SU1498, anti-VEGF-A, or introduction of Vegfr-2(+/-) heterozygosity into Vegfr-1 somatic knockout mice. Upregulation of VEGFR-2 abundance at the protein level contributes in part to increased angiogenesis in VEGFR-1-deficient mice.Circulation 06/2012; 126(6):741-52. · 14.74 Impact Factor -
Article: Prolyl hydroxylase domain protein 2 (PHD2) mediates oxygen-induced retinopathy in neonatal mice.
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ABSTRACT: Retinopathy of prematurity is a major side effect of oxygen therapy for preterm infants, and is a leading cause of blindness in children. To date, it remains unclear whether the initial microvascular obliteration is triggered by degradation of hypoxia inducible factor (HIF) α proteins or by other mechanisms such as oxidative stress. Here we show that prolyl hydroxylase domain protein 2 (PHD2), an enzyme mostly responsible for oxygen-induced degradation of HIF-α proteins, plays a major role in oxygen-induced retinopathy in mice. In neonatal mice expressing normal amounts of PHD2, exposure to 75% oxygen caused significant degradation of retinal HIF-α proteins, accompanied by massive losses of retinal microvessels. PHD2 deficiency significantly stabilized HIF-1α, and to some extent HIF-2α, in neonatal retinal tissues, and protected retinal microvessels from oxygen-induced obliteration. After hyperoxia-treated neonatal mice were returned to ambient room air, retinal vasculature in PHD2-deficient mice remained mostly intact and showed very little neoangiogenesis. These findings demonstrate a close association between PHD2-dependent HIF-α degradation and oxygen-induced retinal microvascular obliteration, and imply that PHD2 may be a promising therapeutic target to prevent oxygen-induced retinopathy.American Journal Of Pathology 04/2011; 178(4):1881-90. · 4.89 Impact Factor -
Chapter: Regulation of Oxygen Homeostasis by Prolyl Hydroxylase Domains
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ABSTRACT: Prolyl hydroxylase domain containing proteins (PHDs) are oxygen sensors critical for the adaptation of multicellular animals to fluctuating oxygen availability in the environment. A key function of PHDs is to catalyze oxygen-dependent prolyl hydroxylation of hypoxia-inducible factor (HIF)-α subunits, a modification that initiates HIF-α degradation. Because HIF-α proteins are transcription factors responsible for the expression of a large number of genes, oxygen regulated HIF-α abundance may enable cells to modify their gene expression programs in accordance to intracellular oxygen concentrations. In addition to HIF-α, the abundance or activity of several other proteins are also regulated by PHD-catalyzed hydroxylation, which suggests that these non-HIF proteins might also contribute to hypoxia responses. Although lower animals such as nematodes have only a single PHD isoform, higher animals such as mammals have multiple PHD or PHD-related proteins to regulate multiple physiological processes, such as angiogenesis, erythropoiesis, and energy metabolism. These features are now being explored to develop novel therapeutic strategies aimed at treating a wide range of diseases such as stroke, heart attack, anemia, inflammation, and cancer. KeywordsProlyl hydroxylase domain containing proteins (PHDs)-Hypoxia-Hypoxia-inducible factors (HIFs)-Angiogenesis12/2010: pages 419-436; -
Article: Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1-/-) attenuates ex vivo myocardial ischemia/reperfusion injury through hypoxia-inducible factor-1α transcription factor and its target genes in mice.
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ABSTRACT: Hypoxia-inducible transcription factor (HIF)-prolyl hydroxylases domain (PHD-1-3) are oxygen sensors that regulate the stability of the HIFs in an oxygen-dependent manner. Suppression of PHD enzymes leads to stabilization of HIFs and offers a potential treatment option for many ischemic disorders, such as peripheral artery occlusive disease, myocardial infarction, and stroke. Here, we show that homozygous disruption of PHD-1 (PHD-1(-/-)) could facilitate HIF-1α-mediated cardioprotection in ischemia/reperfused (I/R) myocardium. Wild-type (WT) and PHD-1(-/-) mice were randomized into WT time-matched control (TMC), PHD-1(-/-) TMC (PHD1TMC), WT I/R, and PHD-1(-/-) I/R (PHD1IR). Isolated hearts from each group were subjected to 30 min of global ischemia followed by 2 h of reperfusion. TMC hearts were perfused for 2 h 30 min without ischemia. Decreased infarct size (35%±0.6% vs. 49%±0.4%) and apoptotic cardiomyocytes (106±13 vs. 233±21 counts/100 high-power field) were observed in PHD1IR compared to wild-type ischemia/reperfusion (WTIR). Protein expression of HIF-1α was significantly increased in PHD1IR compared to WTIR. mRNA expression of β-catenin (1.9-fold), endothelial nitric oxide synthase (1.9-fold), p65 (1.9-fold), and Bcl-2 (2.7-fold) were upregulated in the PHD1IR compared with WTIR, which was studied by real-time quantitative polymerase chain reaction. Further, gel-shift analysis showed increased DNA binding activity of HIF-1α and nuclear factor-kappaB in PHD1IR compared to WTIR. In addition, nuclear translocation of β-catenin was increased in PHD1IR compared with WTIR. These findings indicated that silencing of PHD-1 attenuates myocardial I/R injury probably by enhancing HIF-1α/β-catenin/endothelial nitric oxide synthase/nuclear factor-kappaB and Bcl-2 signaling pathway.Antioxidants & Redox Signaling 11/2010; 15(7):1789-97. · 8.20 Impact Factor -
Article: Integrity of the prolyl hydroxylase domain protein 2:erythropoietin pathway in aging mice.
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ABSTRACT: The central transcriptional response to hypoxia is mediated by the prolyl hydroxylase domain protein (PHD):hypoxia inducible factor (HIF) pathway. In this pathway, PHD prolyl hydroxylates and thereby negatively regulates the alpha-subunit of the transcription factor HIF (HIF-alpha). An important HIF target gene is that for erythropoietin (EPO), which controls red cell mass. Recent studies have identified PHD2 as the critical PHD isoform regulating the EPO gene. Other studies have shown that the inducibility of the HIF pathway diminishes as a function of age. Thus, an important question is whether the PHD2:EPO pathway is altered in the aging. Here, we employed a mouse line with a globally-inducible Phd2 conditional knockout allele to examine the integrity of the Phd2:Epo axis in young (six to eight months old) and aging (sixteen to twenty months old) mice. We find that acute global deletion of Phd2 results in a robust erythrocytosis in both young and aging mice, with both age groups showing marked extramedullary hematopoiesis in the spleen. Epo mRNA is dramatically upregulated in the kidney, but not in the liver, in both age groups. Conversely, other Hif targets, including Vegf, Pgk1, and Phd3 are upregulated in the liver but not in the kidney in both age groups. These findings have implications for targeting this pathway in the aging.Blood Cells Molecules and Diseases 06/2010; 45(1):9-19. · 2.35 Impact Factor -
Article: Cell-based therapy improves cell viability and increases airway size in an explant model.
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ABSTRACT: Cell-based therapy is a promising treatment option for lung disease, but no studies have demonstrated its benefit in promoting perinatal lung growth. Embryonic day 18 (E18) fetal lungs treated with vascular inhibitors were grown as explant organ cultures to inhibit endothelial growth in the explant cultures. Disruption of pulmonary vasculature decreased explant mean cord length and viability, whereas coculture with fetal pulmonary or predifferentiated embryonic stem cells rescued both parameters. These results demonstrate in a model of perinatal lung growth, exogenous addition of fetal pulmonary cells or differentiated embryonic stem (ES) cells promotes survival and alveolar morphogenesis. These experiments represent the first evidence of the benefits of cell-based therapy for perinatal lung growth.Experimental Lung Research 08/2009; 35(6):501-13. · 1.22 Impact Factor -
Article: Efficient derivation of alveolar type II cells from embryonic stem cells for in vivo application.
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ABSTRACT: In the present study, mouse embryonic stem cells (ESCs) were differentiated into alveolar epithelial type II (AEII) cells for endotracheal injection. These enriched lung-like populations expressed lung epithelial markers SP-A, SP-B, SP-C, and CC10. First we show that rapid differentiation of ESCs requires a dissociated seeding method instead of an embryoid body culture method. We then investigated a two-step differentiation of ESCs into definitive endoderm by activin or A549-conditioned medium as a precursor to lung epithelial cells. When conditioned medium from A549 cells was used to derive endoderm, yield was increased above that of activin alone. Further studies showed that Wnt3a may be one of the secreted factors produced by A549 cells and promotes definitive endoderm differentiation, in part, through suppression of primitive endoderm. Activin and Wnt3a together at appropriate doses with dissociated cell seeding promoted greater endoderm yield than activin alone. Next, fibroblast growth factor 2 was shown to induce a dose-dependent expression of SPC, and these cells contained lamellar bodies characteristic of mature AEII cells from ESC-derived endoderm. Finally, ES-derived lung cells were endotracheally injected into preterm mice with evidence of AEII distribution within the lung parenchyma. This study concludes that a recapitulation of development may enhance derivation of an enriched population of lung-like cells for use in cell-based therapy.Tissue Engineering Part A 05/2009; 15(11):3351-65. · 4.64 Impact Factor -
Article: Regulation of angiogenesis by oxygen sensing mechanisms.
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ABSTRACT: The choices for blood vessels to undergo angiogenesis or stay quiescent are mostly determined by the status of tissue oxygenation. A major link between tissue hypoxia and active angiogenesis is the accumulation of hypoxia-inducible factor (HIF)-alpha subunits which play a major role in the transcriptional activation of genes encoding angiogenic factors. HIF-alpha abundance is negatively regulated by a subfamily of dioxygenases referred to as prolyl hydroxylase domain-containing proteins (PHDs) which use O(2) as a substrate to hydroxylate HIF-alpha subunits and hence tag them for rapid degradation. Under hypoxic conditions, HIF-alpha subunits accumulate due to reduced hydroxylation efficiency and form transcriptionally active heterodimers with HIF-1ss to activate the expression of angiogenic factors and other proteins important for cellular adaptation to hypoxia. Angiogenesis is regulated by a combination of at least two different mechanisms. The paracrine mechanism is mediated by non-endothelial expression of angiogenic factors such as vascular endothelial growth factor (VEGF)-A, which in turn interact with endothelial cell surface receptors to initiate angiogenic activities. In the autocrine mechanism, endothelial cell themselves are induced to express VEGF-A, which collaborate with the paracrine mechanism to support angiogenesis and protect vascular integrity. Because of critical roles of PHDs and HIFs in regulating angiogenic activities, studies are underway to assess their candidacy as targets for angiogenesis therapies.Journal of Molecular Medicine 04/2009; 87(6):549-60. · 4.67 Impact Factor -
Article: Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins.
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ABSTRACT: Polycythemia is often associated with erythropoietin (EPO) overexpression and defective oxygen sensing. In normal cells, intracellular oxygen concentrations are directly sensed by prolyl hydroxylase domain (PHD)-containing proteins, which tag hypoxia-inducible factor (HIF) alpha subunits for polyubiquitination and proteasomal degradation by oxygen-dependent prolyl hydroxylation. Here we show that different PHD isoforms differentially regulate HIF-alpha stability in the adult liver and kidney and suppress Epo expression and erythropoiesis through distinct mechanisms. Although Phd1(-/-) or Phd3(-/-) mice had no apparent defects, double knockout of Phd1 and Phd3 led to moderate erythrocytosis. HIF-2alpha, which is known to activate Epo expression, accumulated in the liver. In adult mice deficient for PHD2, the prototypic Epo transcriptional activator HIF-1alpha accumulated in both the kidney and liver. Elevated HIF-1alpha levels were associated with dramatically increased concentrations of both Epo mRNA in the kidney and Epo protein in the serum, which led to severe erythrocytosis. In contrast, heterozygous mutation of Phd2 had no detectable effects on blood homeostasis. These findings suggest that PHD1/3 double deficiency leads to erythrocytosis partly by activating the hepatic HIF-2alpha/Epo pathway, whereas PHD2 deficiency leads to erythrocytosis by activating the renal Epo pathway.Blood 04/2008; 111(6):3229-35. · 9.90 Impact Factor -
Article: Mechanisms of adaptive angiogenesis to tissue hypoxia.
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ABSTRACT: Angiogenesis is mostly an adaptive response to tissue hypoxia, which occurs under a wide variety of situations ranging from embryonic development to tumor growth. In general, angiogenesis is dependent on the accumulation of hypoxia inducible factors (HIFs), which are heterodimeric transcription factors of alpha and beta subunits. Under normoxia, HIF heterodimers are not abundantly present due to oxygen dependent hydroxylation, polyubiquitination, and proteasomal degradation of alpha subunits. Under hypoxia, however, alpha subunits are stabilized and form heterodimers with HIF-1beta which is not subject to oxygen dependent regulation. The accumulation of HIFs under hypoxia allows them to activate the expression of many angiogenic genes and therefore initiates the angiogenic process. In recent years, however, it has become clear that various other mechanisms also participate in fine tuning angiogenesis. In this review, I discuss the relationship between hypoxia and angiogenesis under five topics: (1) regulation of HIF-alpha abundance and activity by oxygen tension and other conditions including oxygen independent mechanisms; (2) hypoxia-regulated expression of angiogenic molecules by HIFs and other transcription factors; (3) responses of vascular cells to hypoxia; (4) angiogenic phenotypes due to altered HIF signaling in mice; and (5) role of the HIF pathway in pathological angiogenesis. Studies discussed under these topics clearly indicate that while mechanisms of oxygen-regulated HIF-alpha stability provide exciting opportunities for the development of angiogenesis or anti-angiogenesis therapies, it is also highly important to consider various other mechanisms for the optimization of these procedures.Angiogenesis 02/2008; 11(2):121-40. · 6.06 Impact Factor -
Article: Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system.
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ABSTRACT: Prolyl hydroxylase domain (PHD) proteins, including PHD1, PHD2, and PHD3, mediate oxygen-dependent degradation of hypoxia-inducible factor (HIF)-alpha subunits. Although angiogenic roles of hypoxia-inducible factors are well known, the roles of PHDs in the vascular system remain to be established. We evaluated angiogenic phenotypes in mice carrying targeted disruptions in genes encoding different PHD isoforms. Although Phd1-/- and Phd3-/- mice did not display apparent angiogenic defects, broad-spectrum conditional knockout of Phd2 led to hyperactive angiogenesis and angiectasia. Blood vessels in PHD2-deficient mice were highly perfusable. Furthermore, examination of medium-sized vessels in subendocardial layer in the heart demonstrated successful recruitment of vascular smooth muscle cells. Surprisingly, increased vascular growth was independent of local efficiency of Phd2 disruption. Mice carrying significant Phd2 disruption in multiple organs, including the liver, heart, kidney, and lung, displayed excessive vascular growth not only in these organs but also in the brain, where Phd2 disruption was very inefficient. More surprisingly, increased accumulation of hypoxia-inducible factor-1alpha and angiectasia in the liver were not accompanied by corresponding increases in hepatic expression of Vegfa or angiopoietin-1. However, the serum vascular endothelial growth factor-A level was significantly increased in PHD2-deficient mice. PHD2, but not PHD1 and PHD3, is a major negative regulator for vascular growth in adult mice. Increased angiogenesis in PHD2-deficient mice may be mediated by a novel systemic mechanism.Circulation 09/2007; 116(7):774-81. · 14.74 Impact Factor -
Article: Prolyl hydroxylase domain 2 protein suppresses hypoxia-induced endothelial cell proliferation.
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ABSTRACT: Prolyl hydroxylase domain 2 protein (PHD2) signals the degradation of hypoxia-inducible factor (HIF)-1alpha by hydroxylating specific prolyl residues located within oxygen-dependent degradation domains. As expected, endothelial cells (ECs) overexpressing PHD2 had reduced HIF-1alpha and vascular endothelial growth factor-A expression and failed to accelerate their proliferation in response to hypoxia. Surprisingly, although these cells displayed further reductions in HIF-1alpha and vascular endothelial growth factor-A expression when cultured under normoxia, there was no further reduction in EC proliferation. Thus, there seemed to be no consistent correlation between PHD2 hydroxylase-mediated suppression of HIF-1alpha expression and inhibition of EC growth. Indeed, overexpression of a mutant PHD2 lacking hydroxylase activity also greatly diminished EC response to hypoxia-induced increase in proliferation, in spite of the fact that hypoxia-induced HIF-1alpha accumulation was not affected by mutant PHD2. These data strongly suggest the existence of a hydroxylase-independent mechanism for PHD2-mediated inhibition of EC proliferation under hypoxia. In support of a physiological relevance of PHD2 overexpression, we found that endogenous PHD2 expression was significantly upregulated by hypoxia and that silencing of the Phd2 gene by RNA interference significantly enhanced hypoxia-induced EC proliferation. In conclusion, this study demonstrates that PHD2 may act as a negative feedback regulator to antagonize hypoxia-induced EC proliferation.Hypertension 02/2007; 49(1):178-84. · 6.21 Impact Factor -
Article: Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2.
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ABSTRACT: PHD1, PHD2, and PHD3 are prolyl hydroxylase domain proteins that regulate the stability of hypoxia-inducible factor alpha subunits (HIF-alpha). To determine the roles of individual PHDs during mouse development, we disrupted all three Phd genes and found that Phd2(-/-) embryos died between embryonic days 12.5 and 14.5 whereas Phd1(-/-) or Phd3(-/-) mice were apparently normal. In Phd2(-/-) mice, severe placental and heart defects preceded embryonic death. Placental defects included significantly reduced labyrinthine branching morphogenesis, widespread penetration of the labyrinth by spongiotrophoblasts, and abnormal distribution of trophoblast giant cells. The expression of several trophoblast markers was also altered, including an increase in the spongiotrophoblast marker Mash2 and decreases in the labyrinthine markers Tfeb and Gcm1. In the heart, trabeculae were poorly developed, the myocardium was remarkably thinner, and interventricular septum was incompletely formed. Surprisingly, while there were significant global increases in HIF-alpha protein levels in the placenta and the embryo proper, there was no specific HIF-alpha increase in the heart. Taken together, these data indicate that among all three PHD proteins, PHD2 is uniquely essential during mouse embryogenesis.Molecular and Cellular Biology 12/2006; 26(22):8336-46. · 5.53 Impact Factor -
Article: Endothelium-intrinsic requirement for Hif-2alpha during vascular development.
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ABSTRACT: The development of the vascular system is a complex process that involves communications among multiple cell types. As such, it is important to understand whether a specific gene regulates vascular development directly from within the vascular system or indirectly from nonvascular cells. Hypoxia-inducible factor-2alpha (Hif-2alpha, or endothelial PAS protein-1 [EPAS-1]) is required for vascular development in mice, but it is not clear whether its requirement resides directly in endothelial cells. To address this issue, we expressed Hif-2alpha cDNA in the vascular endothelium of Hif-2alpha-/- embryos by an embryonic stem (ES) cell-mediated transgenic approach and assessed whether endothelium-specific reexpression of Hif-2alpha could rescue vascular development. Here we report that although ES cell-derived Hif-2alpha-/- embryos developed severe vascular defects by embryonic day (E) 11.5 and died in utero before E12.5, endothelium-specific expression of Hif-2alpha cDNA restored normal vascular development at all stages examined (up to E14.5) and allowed Hif-2alpha-/- embryos to survive at a frequency comparable to that of Hif-2alpha+/- embryos. Furthermore, we found that Tie-2 expression was significantly reduced in Hif-2alpha-/- mutants but was restored by Hif-2alpha cDNA expression. These data demonstrate an intrinsic requirement for Hif-2alpha by endothelial cells and imply that hypoxia may control endothelial functions directly via Hif-2alpha-regulated Tie-2 expression.Circulation 06/2005; 111(17):2227-32. · 14.74 Impact Factor -
Article: Deficiency in the p110alpha subunit of PI3K results in diminished Tie2 expression and Tie2(-/-)-like vascular defects in mice.
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ABSTRACT: Phosphoinositide 3-kinase (PI3K) is activated by transmembrane tyrosine kinases such as vascular endothelial growth factor (VEGF) receptors and Tie2 (tunica intima endothelial kinase 2), both of which are key regulators of vascular development. However, the in vivo role of PI3K during developmental vascularization remains to be defined. Here we demonstrate that mice deficient in the p110alpha catalytic subunit of PI3K display multiple vascular defects, including dilated vessels in the head, reduced branching morphogenesis in the endocardium, lack of hierarchical order of large and small branches in the yolk sac, and impaired development of anterior cardinal veins. These vascular defects are strikingly similar to those in mice defective in the Tie2 signaling pathway. Indeed, Tie2 protein levels were significantly lower in p110alpha-deficient mice. Furthermore, RNA interference of p110alpha in cultured endothelial cells significantly reduced Tie2 protein levels. These findings raise the possibility that PI3K may function as an upstream regulator of Tie2 expression during mouse development.Blood 06/2005; 105(10):3935-8. · 9.90 Impact Factor -
Article: Ischemic preconditioning-mediated cardioprotection is disrupted in heterozygous Flt-1 (VEGFR-1) knockout mice.
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ABSTRACT: This study attempts to address an important clinical issue by identifying potential candidates of VEGF signaling through Flt-1 receptor that trigger angiogenic signal under ischemic stress. To determine the significance of VEGF-Flt-1 (VEGFR1) signaling in ischemic preconditioned (PC) myocardium, we used heterozygous Flt-1 knockout (KO) mice to dissect the pathway and identify candidate genes involved in VEGF signaling. DNA microarrays were employed to detect, characterize and distinguish altered myocardial gene expression by comparing between wild type (WT) CD-1 and heterozygous Flt-1 KO mice when exposed to ischemia (30 min) and reperfusion (2 h). Moreover, KO mice demonstrated reduced beneficial effects of PC when compared to the WT with PC. In the KO and WT mice, the % recovery of the left ventricular developed pressure and the maximum first derivative of the developed pressure after ischemia/reperfusion without PC were similar. However, when animals were subjected to PC, the left ventricular functional recovery throughout the reperfusion period was significantly lower in KO mice than in WT mice. These results indicate for the first time that in the heterozygous Flt-1 KO mice, PC is not as effective as that found in WT. This observation may be due to downregulation of several important genes such as growth-regulated oncogene 1 (Gro1), heat shock proteins (HSP), I kappa B kinase beta (IKK beta), colony-stimulating factor-1 (CSF-1) and annexin A7, suggesting the importance of VEGF-Flt-1 receptor signaling during PC.Journal of Molecular and Cellular Cardiology 03/2005; 38(2):345-51. · 5.17 Impact Factor -
Article: Dual roles of the C-terminal Src kinase (Csk) during developmental vascularization.
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ABSTRACT: Here we report that C-terminal Src kinase (Csk), a tyrosine kinase that negatively regulates the activity of Src and related kinases, is important for vascular development. In Csk(-/-) embryos, although vascular tubules were formed and organized into capillary-like networks during the initial genesis of blood vessels, the vessels failed to engage in normal sprout formation. In chimeric embryos containing both wild-type and Csk(-/-) cells, the presence of wild-type cells enabled Csk(-/-) endothelial cells to participate in branching morphogenesis. We suggest that wild-type cells may have supplied an angiogenic factor absent in Csk(-/-) cells. Despite the partial rescue of vascular development in chimeric embryos, the embryos failed to form vitelline vessels and died at E9.5. These results indicate that Csk is required both for angiogenic sprouting and vascular remodeling.Blood 03/2004; 103(4):1370-2. · 9.90 Impact Factor -
Article: Gastrulation and angiogenesis, not endothelial specification, is sensitive to partial deficiency in vascular endothelial growth factor-a in mice.
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ABSTRACT: Mouse embryogenesis is dose sensitive to vascular endothelial growth factor-A (VEGF-A), and mouse embryos partially deficient in VEGF-A die in utero because of severe vascular defects. In this study, we investigate the possible causes that underlie this phenomenon. Although the development of vascular defects in VEGF-A-deficient embryos seems to suggest that endothelial differentiation depends on the presence of a sufficient level of VEGF-A, we were surprised to find that endothelial differentiation per se is insensitive to a significant loss of VEGF-A activity. Instead, the development of the multipotent mesenchymal cells, from which endothelial progenitors arise in the yolk sac, is most highly dependent on VEGF-A. As a result of VEGF-A deficiency, dramatically fewer multipotent mesenchymal cells are generated in the prospective yolk sac. However, among the small number of mesenchymal cells that do enter the prospective yolk sac, endothelial differentiation occurs at a normal frequency. In the embryo proper, vasculogenesis is initiated actively in spite of a significant VEGF-A deficiency, but the subsequent steps of vascular development are defective. We conclude that a full-level VEGF-A activity is not critical for endothelial specification but is important for two distinct processes before and after endothelial specification: the development of the yolk sac mesenchyme and angiogenic sprouting of blood vessels.Biology of Reproduction 01/2004; 69(6):1852-8. · 4.01 Impact Factor
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2008–2009
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UConn Health Center
Farmington, CT, USA
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