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  • 1
    Online Resource
    Online Resource
    CYP1B1 expression promotes the proangiogenic phenotype of endothelium through decreased intracellular oxidative stress and thrombospondin-2 expression
    American Society of Hematology ; 2009
    In:  Blood Vol. 113, No. 3 ( 2009-01-15), p. 744-754
    Details
    In: Blood, American Society of Hematology, Vol. 113, No. 3 ( 2009-01-15), p. 744-754
    Abstract: Reactive species derived from cell oxygenation processes play an important role in vascular homeostasis and the pathogenesis of many diseases including retinopathy of prematurity. We show that CYP1B1-deficient (CYP1B1−/−) mice fail to elicit a neovascular response during oxygen-induced ischemic retinopathy. In addition, the retinal endothelial cells (ECs) prepared from CYP1B1−/− mice are less adherent, less migratory, and fail to undergo capillary morphogenesis. These aberrant cellular responses were completely reversed when oxygen levels were lowered or an antioxidant added. CYP1B1−/− ECs exhibited increased oxidative stress and expressed increased amounts of the antiangiogenic factor thrombospondin-2 (TSP2). Increased lipid peroxidation and TSP2 were both observed in retinas from CYP1B1−/− mice and were reversed by administration of an antioxidant. Reexpression of CYP1B1 in CYP1B1−/− ECs resulted in down-regulation of TSP2 expression and restoration of capillary morphogenesis. A TSP2 knockdown in CYP1B1−/− ECs also restored capillary morphogenesis. Thus, CYP1B1 metabolizes cell products that modulate intracellular oxidative stress, which enhances production of TSP2, an inhibitor of EC migration and capillary morphogenesis. Evidence is presented that similar changes occur in retinal endothelium in vivo to limit neovascularization.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2008-03-145219
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    Online Resource
    Online Resource
    CYP1B1 and endothelial nitric oxide synthase combine to sustain proangiogenic functions of endothelial cells under hyperoxic stress
    American Physiological Society ; 2010
    In:  American Journal of Physiology-Cell Physiology Vol. 298, No. 3 ( 2010-03), p. C665-C678
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 298, No. 3 ( 2010-03), p. C665-C678
    Abstract: We have recently shown that deletion of constitutively expressed CYP1B1 is associated with attenuation of retinal endothelial cell (EC) capillary morphogenesis (CM) in vitro and angiogenesis in vivo. This was largely caused by increased intracellular oxidative stress and increased production of thrombospondin-2, an endogenous inhibitor of angiogenesis. Here, we demonstrate that endothelium nitric oxide synthase (eNOS) expression is dramatically decreased in the ECs prepared from retina, lung, heart, and aorta of CYP1B1-deficient (CYP1B1 −/− ) mice compared with wild-type (CYP1B1 +/+ ) mice. The eNOS expression was also decreased in retinal vasculature of CYP1B1 −/− mice. Inhibition of eNOS activity in cultured CYP1B1 +/+ retinal ECs blocked CM and was concomitant with increased oxidative stress, like in CYP1B1 −/− retinal ECs. In addition, expression of eNOS in CYP1B1 −/− retinal ECs or their incubation with a nitric oxide (NO) donor enhanced NO levels, lowered oxidative stress, and improved cell migration and CM. Inhibition of CYP1B1 activity in the CYP1B1 +/+ retinal ECs resulted in reduced NO levels and attenuation of CM. In contrast, expression of CYP1B1 increased NO levels and enhanced CM of CYP1B1 −/− retinal ECs. Furthermore, attenuation of CYP1B1 expression with small interfering RNA proportionally lowered eNOS expression and NO levels in wild-type cells. Together, our results link CYP1B1 metabolism in retinal ECs with sustained eNOS activity and NO synthesis and/or bioavailability and low oxidative stress and thrombospondin-2 expression. Thus CYP1B1 and eNOS cooperate in different ways to lower oxidative stress and thereby to promote CM in vitro and angiogenesis in vivo.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00153.2009
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2010
    detail.hit.zdb_id: 1477334-X
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  • 3
    Online Resource
    Online Resource
    Opposing effects of bim and bcl-2 on lung endothelial cell migration
    American Physiological Society ; 2010
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 299, No. 5 ( 2010-11), p. L607-L620
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 299, No. 5 ( 2010-11), p. L607-L620
    Abstract: Integration of cell adhesive, survival, and proliferative processes is essential for capillary morphogenesis of endothelial cells (EC) in vitro and vascular development and function in vivo. Unfortunately, the molecular and cellular mechanisms that impact these processes are poorly defined. Here we examined how lack of bim and/or bcl-2 expression impact lung EC function. The absence of bcl-2 or bim had a significant impact on EC adhesion and migration. Lack of bcl-2 expression decreased lung EC migration, whereas lack of bim expression increased migration compared with their wild-type counterparts. Decreased adhesion to fibronectin and vitronectin was observed in both bcl-2−/− and bim−/− lung EC, with bcl-2−/− EC having very little adhesion to either matrix protein. Capillary morphogenesis was greatly diminished in bcl-2−/− EC, which correlated with decreased lung alveolarization in vivo, an angiogenesis-dependent process. We also observed aberrant production of extracellular matrix proteins, eNOS expression, and nitric oxide production in bcl-2−/− lung EC, which could contribute to inability to undergo capillary morphogenesis. The changes in cell adhesion and migration noted in the absence of bim or bcl-2 were independent of their impact on apoptosis. We observed no significant affect on the steady-state rate of apoptosis of lung EC in the absence of bim or bcl-2. Thus, bcl-2 family members, bim and bcl-2, play a central role in modulation of EC proangiogenic properties, which goes beyond their role as simple mediators of mitochondrial homeostasis and apoptosis.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00390.2009
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2010
    detail.hit.zdb_id: 1477300-4
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  • 4
    Online Resource
    Online Resource
    PECAM-1 isoform-specific regulation of kidney endothelial cell migration and capillary morphogenesis
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Cell Physiology Vol. 292, No. 6 ( 2007-06), p. C2070-C2083
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 292, No. 6 ( 2007-06), p. C2070-C2083
    Abstract: Platelet endothelial cell adhesion molecule-1 (PECAM-1) has been implicated in angiogenesis through its involvement in endothelial cell-cell and cell-matrix interactions and signal transduction. Recent studies indicate that the cytoplasmic domain of PECAM-1 plays an important role in its cell adhesive and signaling properties. However, the role PECAM-1 isoforms play during angiogenic events such as cell adhesion and migration requires further delineation. To gain insight into the role PECAM-1 plays during vascular development and angiogenesis, we examined the expression pattern of PECAM-1 isoforms during kidney vascularization. We show that multiple isoforms of PECAM-1 are expressed during renal vascular development with different frequencies. The PECAM-1 that lacks exons 14 and 15 (Δ14 & 15) was the predominant isoform detected in the renal vasculature. To further study PECAM-1 isoform-specific functions we isolated kidney endothelial cells (EC) from wild-type and PECAM-1-deficient (PECAM-1−/−) mice with B 4 -lectin-coated magnetic beads. PECAM-1−/− kidney EC showed reduced migration, inability to undergo capillary morphogenesis in Matrigel, dense peripheral focal adhesions, and peripheral cortical actin distribution compared with wild-type cells. PECAM-1−/− kidney EC secreted increased amounts of fibronectin and decreased amounts of tenascin-C and thrombospondin-1. Reexpression of Δ14 & 15, but not full-length, PECAM-1 in PECAM-1−/− kidney EC restored cell migration and capillary morphogenesis defects. Thus PECAM-1 may regulate the adhesive and migratory properties of kidney EC in an isoform-specific fashion through modulation of integrin activity and extracellular matrix protein expression. Our results indicate that regulated expression of specific PECAM-1 isoforms may enable EC to accommodate the different stages of angiogenesis.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00489.2006
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477334-X
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  • 5
    Online Resource
    Online Resource
    Attenuation of retinal vascular development and neovascularization in PECAM-1-deficient mice
    Elsevier BV ; 2008
    In:  Developmental Biology Vol. 315, No. 1 ( 2008-03), p. 72-88
    Details
    In: Developmental Biology, Elsevier BV, Vol. 315, No. 1 ( 2008-03), p. 72-88
    Type of Medium: Online Resource
    ISSN: 0012-1606
    URL: Article
    DOI: 10.1016/j.ydbio.2007.12.008
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
    detail.hit.zdb_id: 1463203-2
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  • 6
    Online Resource
    Online Resource
    A fluorescence polarization assay for identifying ligands that bind to vascular endothelial growth factor
    Elsevier BV ; 2008
    In:  Analytical Biochemistry Vol. 378, No. 1 ( 2008-07), p. 8-14
    Details
    In: Analytical Biochemistry, Elsevier BV, Vol. 378, No. 1 ( 2008-07), p. 8-14
    Type of Medium: Online Resource
    ISSN: 0003-2697
    URL: Article
    DOI: 10.1016/j.ab.2008.03.043
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
    detail.hit.zdb_id: 1461105-3
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  • 7
    Online Resource
    Online Resource
    Bcl‐2 expression modulates cell adhesion and migration promoting branching of ureteric bud cells
    Wiley ; 2007
    In:  Journal of Cellular Physiology Vol. 210, No. 3 ( 2007-03), p. 616-625
    Details
    In: Journal of Cellular Physiology, Wiley, Vol. 210, No. 3 ( 2007-03), p. 616-625
    Abstract: Bcl‐2 is the founding member of a family of proteins that influence apoptosis. During kidney development bcl‐2 not only acts as a survival factor, but may also impact cell adhesive mechanisms and by extension branching morphogenesis. The interrelationship between cell adhesion, migration and apoptosis, important during development, is poorly understood. Here we examined the impact lack of bcl‐2, an inhibitor of apoptosis, has on ureteric bud (UB) cell adhesion, migration, and branching morphogenesis. Bcl‐2 −/− UB cells demonstrated increased cell migration, increased cell invasion and decreased adhesion to vitronectin and fibronectin compared with wild‐type cells. Bcl‐2 +/+ UB cells readily branched in collagen gel and Matrigel while bcl‐2 −/− UB cells did not undergo significant branching in either matrix. Re‐expression of bcl‐2 in bcl‐2 −/− UB cells restored their ability to undergo branching morphogenesis in Matrigel. Consistent with our in vitro data, we show that in the absence of bcl‐2, embryonic kidneys undergo decreased UB branching. We observed decreased numbers of UB branch points, UB branch tips and a decreased distance to the first UB branch point in the absence of bcl‐2. The alterations in bcl‐2 −/− UB cell adhesion and migration was also associated with a significant alteration in expression of a number of extracellular matrix proteins. Bcl‐2 −/− UB cells exhibited increased fibronectin expression and decreased thrombospondin‐1 and osteopontin expression. Taken together, these data suggest that bcl‐2 is required for the proper regulation of cell adhesive and migratory mechanisms, perhaps through modulation of the cellular microenvironment. J. Cell. Physiol. 210: 616–625, 2007. © 2006 Wiley‐Liss, Inc.
    Type of Medium: Online Resource
    ISSN: 0021-9541 , 1097-4652
    URL: Issue
    URL: Article
    DOI: 10.1002/jcp.v210:3
    DOI: 10.1002/jcp.20858
    Language: English
    Publisher: Wiley
    Publication Date: 2007
    detail.hit.zdb_id: 1478143-8
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  • 8
    Online Resource
    Online Resource
    Attenuation of proliferation and migration of retinal pericytes in the absence of thrombospondin-1
    American Physiological Society ; 2009
    In:  American Journal of Physiology-Cell Physiology Vol. 296, No. 4 ( 2009-04), p. C724-C734
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 296, No. 4 ( 2009-04), p. C724-C734
    Abstract: Perivascular supporting cells, including vascular smooth muscle cells (VSMCs) and pericytes (PCs), provide instructive signals to adjacent endothelial cells helping to maintain vascular homeostasis. These signals are provided through direct contact and by the release of soluble factors by these cells. Thrombospondin (TSP)1 is a matricellular protein and an autocrine factor for VSMCs. TSP1 activity, along with that of PDGF, regulates VSMC proliferation and migration. However, the manner in which TSP1 and PDGF impact retinal PC function requires further investigation. In the present study, we describe, for the first time, the isolation and culture of retinal PCs from wild-type (TSP1 +/+ ) and TSP1-deficient (TSP1 −/− ) immortomice. We showed that these cells express early and mature markers of PCs, including NG2, PDGF receptor-β, and smooth muscle actin as well as desmin, calbindin, and mesenchymal stem cell markers. These cells were successfully passaged and maintained in culture for several months without significant loss of expression of these markers. TSP1 +/+ PCs proliferated at a faster rate compared with TSP1 −/− PCs. In addition, TSP1 +/+ PCs, like VSMCs, responded to PDGF-BB with enhanced migration and proliferation. In contrast, TSP1 −/− PCs failed to respond to the promigratory and proliferative activity of PDGF-BB. This may be attributed, at least in part, to the limited interaction of PDGF-BB with TSP1 in null cells, which is essential for PDGF proliferative and migratory action. We observed no significant differences in the rates of apoptosis in these cells. TSP1 −/− PCs were also less adherent, expressed increased levels of TSP2 and fibronectin, and had decreased amounts of N-cadherin and α v β 3 -integrin on their surface. Thus, TSP1 plays a significant role in retinal PC proliferation and migration impacting retinal vascular development and homeostasis.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00409.2008
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2009
    detail.hit.zdb_id: 1477334-X
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  • 9
    Online Resource
    Online Resource
    PECAM-1 regulates proangiogenic properties of endothelial cells through modulation of cell-cell and cell-matrix interactions
    American Physiological Society ; 2010
    In:  American Journal of Physiology-Cell Physiology Vol. 299, No. 6 ( 2010-12), p. C1468-C1484
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 299, No. 6 ( 2010-12), p. C1468-C1484
    Abstract: Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) is a member of the immunoglobulin superfamily of cell adhesion molecules with important roles in angiogenesis and inflammation. However, the molecular and cellular mechanisms, and the role that specific PECAM-1 isoforms play in these processes, remain elusive. We recently showed attenuation of retinal vascular development and neovascularization in PECAM-1-deficient (PECAM-1−/−) mice. To gain further insight into the role of PECAM-1 in these processes, we isolated primary retinal endothelial cells (EC) from wild-type (PECAM-1+/+) and PECAM-1−/− mice. Lack of PECAM-1 had a significant impact on endothelial cell-cell and cell-matrix interactions, resulting in attenuation of cell migration and capillary morphogenesis. Mechanistically these changes were associated with a significant decrease in expression of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) bioavailability in PECAM-1−/− retinal EC. PECAM-1−/− retinal EC also exhibited a lower rate of apoptosis under basal and challenged conditions, consistent with their increased growth rate. Furthermore, reexpression of PECAM-1 was sufficient to restore migration and capillary morphogenesis of null cells in an isoform-specific manner. Thus PECAM-1 expression modulates proangiogenic properties of EC, and these activities are significantly influenced by alternative splicing of its cytoplasmic domain.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00246.2010
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2010
    detail.hit.zdb_id: 1477334-X
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  • 10
    Online Resource
    Online Resource
    Attenuation of retinal endothelial cell migration and capillary morphogenesis in the absence of bcl-2
    American Physiological Society ; 2008
    In:  American Journal of Physiology-Cell Physiology Vol. 294, No. 6 ( 2008-06), p. C1521-C1530
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 294, No. 6 ( 2008-06), p. C1521-C1530
    Abstract: Apoptosis plays a critical role during development and in the maintenance of the vascular system. B-cell leukemia lymphoma 2 (bcl-2) protects endothelial cells (EC) from apoptosis in response to a variety of stimuli. Previous work from this laboratory demonstrated attenuation of postnatal retinal vascular development and retinal neovascularization during oxygen-induced ischemic retinopathy in bcl-2-deficient (bcl-2 −/− ) mice. To gain further insight into the function of bcl-2 in the endothelium, we isolated retinal EC from bcl-2 +/+ and bcl-2 −/− mice. Retinal EC lacking bcl-2 demonstrated reduced cell migration, tenascin-C expression, and adhesion to vitronectin and fibronectin. The bcl-2 −/− retinal EC also failed to undergo capillary morphogenesis in Matrigel. In addition, using an ex vivo angiogenesis assay, we observed reduced sprouting from aortic rings grown in culture from bcl-2 −/− mice compared with bcl-2 +/+ mice. Furthermore, reexpression of bcl-2 was sufficient to restore migration and capillary morphogenesis defects observed in bcl-2 −/− retinal EC. Mechanistically, bcl-2 −/− cells expressed significantly less endothelial nitric oxide synthase, an important downstream effecter of proangiogenic signaling. This may be attributed to increased oxidative stress in the absence of bcl-2. In fact, incubation of retinal EC or aortic rings from bcl-2 −/− mice with the antioxidant N-acetylcysteine rescued their capillary morphogenesis and sprouting defects. Thus, bcl-2-mediated cellular functions play important roles not only in survival but also in proangiogenic phenotype of EC with a significant impact on vascular development and angiogenesis.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.90633.2007
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
    detail.hit.zdb_id: 1477334-X
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