CYP1B1 and endothelial nitric oxide synthase combine to sustain proangiogenic functions of endothelial cells under hyperoxic stress

Tang, Yixin; Scheef, Elizabeth A.; Gurel, Zafer; Sorenson, Christine M.; Jefcoate, Colin R.; Sheibani, Nader

doi:10.1152/ajpcell.00153.2009

Cited by 50 publications

(50 citation statements)

References 63 publications

(91 reference statements)

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“…Thus expression of VEGF by itself was not sufficient to activate eNOS and enhance NO production and angiogenesis. These observations are consistent with our recent studies (44) in which we showed that incubation of PECAM-1ϩ/ϩ retinal EC with nitro-Larginine methyl ester (L-NAME, eNOS inhibitor), but not nitro-D-arginine methyl ester (D-NAME, inactive analog), attenuates capillary morphogenesis. Thus appropriate expression and activity of eNOS and NO bioavailability are significantly influenced by PECAM-1 expression and/or activity.…”

Section: Discussionsupporting

confidence: 93%

PECAM-1 regulates proangiogenic properties of endothelial cells through modulation of cell-cell and cell-matrix interactions

Park

DiMaio

Scheef

et al. 2010

American Journal of Physiology-Cell Physiology

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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.

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Section: Discussionsupporting

confidence: 93%

PECAM-1 regulates proangiogenic properties of endothelial cells through modulation of cell-cell and cell-matrix interactions

Park

DiMaio

Scheef

et al. 2010

American Journal of Physiology-Cell Physiology

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“…Perhaps, the co-localization of endoglin and eNOS in caveolae regulates NO production. Our results indicate that endoglin haploinsufficiency is associated with decreased eNOS expression, NO production and attenuation of EC capillary morphogenesis, as previously demonstrated (Tang et al, 2010). How endoglin haploinsufficiency contributes to aberrant regulation of eNOS expression and/or NO production is subject of current investigation in our laboratory.…”

Section: Discussionsupporting

confidence: 84%

Endoglin Regulates the Activation and Quiescence of Endothelium by Participating in Canonical and Non-Canonical TGF-β Signaling Pathways

Park¹,

DiMaio²,

Liu³

et al. 2013

Journal of Cell Science

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SummaryEndoglin (Eng) is an auxiliary receptor for transforming growth factor-b (TGFb), with important roles in vascular function. TGFb regulates angiogenesis through balancing the pro-proliferative and pro-differentiation signaling pathways of endothelial cells (EC). However, the contribution of endoglin to these TGFb activities, and more specifically modulation of EC phenotype, remains elusive. Mutations in endoglin cause hereditary hemorrhagic telangiectasia-1 in humans. The Eng+/2 mice are viable and exhibit some of the vascular defects seen in humans with endoglin haploinsufficiency. In the present study we show that haploinsufficiency of endoglin results in attenuation of retinal neovascularization during oxygen-induced ischemic retinopathy. Although the importance of endoglin expression in angiogenesis and vascular development has been demonstrated, the underlying mechanisms remain obscure. To gain detailed insight into the cell autonomous regulatory mechanisms that affect angiogenic properties of EC, we prepared retinal EC from Eng+/+ and Eng+/2 Immorto mice. The Eng+/2 EC were more adherent, less migratory, and failed to undergo capillary morphogenesis. Aortic sprouting angiogenesis was similarly attenuated in aortas from Eng+/2 mice. In addition, Eng+/2 EC expressed increased levels of VEGF but reduced expression of endothelial NO synthase and NO production. Mechanistically, these changes were consistent with sustained activation of mitogen-activated protein kinase (MAPK) pathways, and aberrant Smad-dependent signaling pathways in Eng+/2 EC. Taken together, our results underscore the importance of endoglin in both canonical and non-canonical TGFb signaling pathways modulating both the activation and quiescence of the endothelium during angiogenesis.

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“…The ability of NO to regulate TSP2 expression has not been reported previously. However, a link between oxidative stress and TSP2 has been established in a model in which deletion of CYP1B1 resulted in increased ROS and TSP2 in retinal-derived ECs, which was reversed with an antioxidant (25,43). Moreover, TSP2 redox sensitivity is confirmed by the observation that Rac1-induced ROS increased TSP2 in human aortic endothelial cells (HAECs) (26).…”

Section: Tsp2 Deficiency Rescues the Enos-ko Phenotype In Ischemia Andmentioning

confidence: 99%

Endothelial nitric oxide synthase controls the expression of the angiogenesis inhibitor thrombospondin 2

MacLauchlan

Yu²,

Parrish³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Injury-and ischemia-induced angiogenesis is critical for tissue repair and requires nitric oxide (NO) derived from endothelial nitric oxide synthase (eNOS). We present evidence that NO induces angiogenesis by modulating the level of the angiogenesis inhibitor thrombospondin 2 (TSP2). TSP2 levels were higher than WT in eNOS KO tissues in hind-limb ischemia and cutaneous wounds. In vitro studies confirmed that NO represses TSP2 promoter activity. Moreover, double-eNOS/TSP2 KO mice were generated and found to rescue the phenotype of eNOS KO mice. Studies in mice with knock-in constitutively active or inactive eNOS on the Akt-1 KO background showed that eNOS activity correlates with TSP2 levels. Our observations of NO-mediated regulation of angiogenesis via the suppression of TSP2 expression provide a description of improved eNOS KO phenotype by means other than restoring NO signaling.wound healing | extracellular matrix | Akt | matrix metalloproteinases E ndothelial nitric oxide synthase (eNOS) and its bioactive product nitric oxide (NO) are well-established proangiogenic molecules. Endothelial-derived NO is crucial for maintenance of proper vasodilatory tone and regulation of an antiproliferative and antiapoptotic state for endothelial cells (ECs) and has essential roles in physiological angiogenesis (1-3). Pharmacological inhibition or genetic disruption of eNOS limited angiogenesis during tissue repair, resulting in delayed wound closure (2, 4). Addition of NO donors to wounds enhanced angiogenesis and accelerated healing (5-7). eNOS KO mice recovered poorly from hind-limb ischemia as a consequence of decreased angiogenesis (3,8). These mice also displayed accelerated atherosclerosis, neointimal thickening postinjury, and hypertension (1, 9). Taken together, these observations highlight the ability of eNOS-derived NO to influence vascular function.Thrombospondins (TSPs) are a small family of antiangiogenic matricellular proteins (10). TSPs enhance clearance of matrix metalloproteinase (MMP)-2 and MMP-9 (11-13) and interact with cell-surface receptors, including α v β 3 , very low density lipoprotein receptor (VLDLR), CD36, and CD47, to inhibit angiogenesis (14). Further, ultrastructural studies demonstrated that TSP2 influences ECM assembly (15, 16). TSP2 KO mice displayed improved recovery of blood flow following ischemia (17), altered foreign body response (18,19), and accelerated wound healing (16,20,21). In contrast, TSP1 KO mice displayed delayed healing because of insufficient stimulation of inflammation (13). Consistent with these observations, the expression of TSP1 and TSP2 in tissue repair was associated with the inflammatory and repair phases, respectively (13, 16). Recently, several studies linked components of the Akt-eNOS cascade with TSPs. Specifically, TSP1 has been described to blunt the ability of NO to activate soluble guanyl cyclase (sGC) (22, 23) through interactions with CD36 and CD47 during ischemia. TSP1 has also been described to diminish eNOS activity by blocking phosphorylation at S117...

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CYP1B1 and endothelial nitric oxide synthase combine to sustain proangiogenic functions of endothelial cells under hyperoxic stress

Cited by 50 publications

References 63 publications

PECAM-1 regulates proangiogenic properties of endothelial cells through modulation of cell-cell and cell-matrix interactions

PECAM-1 regulates proangiogenic properties of endothelial cells through modulation of cell-cell and cell-matrix interactions

Endoglin Regulates the Activation and Quiescence of Endothelium by Participating in Canonical and Non-Canonical TGF-β Signaling Pathways

Endothelial nitric oxide synthase controls the expression of the angiogenesis inhibitor thrombospondin 2

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