Strain-dependent anterior segment neovascularization following intravitreal gene transfer of basic fibroblast growth factor (bFGF)

Gupta, Abha R.; Dejneka, Nadine S.; D’Amato, Robert J.; Yang, Zeyong; Syed, Nasreen A.; Maguire, Albert M.; Bennett, Jean

doi:10.1002/1521-2254(200105/06)3:3<252::aid-jgm185>3.0.co;2-s

Cited by 18 publications

(16 citation statements)

References 22 publications

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“…The median vessel densities in the retinas of animals with EIIIB deletion and EIIIA deletion were 21 and 14.5 fluorescence units per 100 pixels, respectively. This difference in vessel density is probably due to strain-specific genetic factors that influence angiogenic response (22,49). Since EIIIA-containing FNs have been implicated in vascular smooth muscle cell differentiation, we examined smooth muscle coverage of tail arteries in cross sections of tails from 7-day-old mice (50).…”

Section: Resultsmentioning

confidence: 99%

Direct Test of Potential Roles of EIIIA and EIIIB Alternatively Spliced Segments of Fibronectin in Physiological and Tumor Angiogenesis

Astrof

Crowley

George

et al. 2004

Molecular and Cellular Biology

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Fibronectin splice variants containing the EIIIA and/or EIIIB exons are prominently expressed in the vasculature of a variety of human tumors but not in normal adult tissues. To understand the functions of these splice variants in physiological and tumor angiogenesis, we used EIIIB-null and EIIIA-null strains of mice to examine neovascularization of mouse retinas, pancreatic tumors in Rip-Tag transgenic mice, and transplanted melanomas. Contrary to expectations, physiological and tumor angiogenesis was not significantly affected by the absence of either EIIIA or EIIIB splice variants. Tumor growth was also not affected. In addition, the expression levels of smooth muscle alpha actin, believed to be modulated by EIIIA-containing fibronectins, were not affected either. Our experiments show that despite their tight regulation during angiogenesis, the presence of EIIIA or EIIIB splice variants individually is not essential for neovascularization.Angiogenesis is a process whereby new blood vessels develop from the preexisting vasculature (5). This process is crucial to provide oxygen and nutrients to a growing tumor mass; without a vascular supply, tumors fail to grow beyond 1.5 mm in diameter (15,25). Inhibition of tumor angiogenesis leads to inhibition or retardation of tumor growth in animal tumor models (7). The extracellular milieu plays a prominent role in tumor development by supplying factors that can either enhance (e.g., matrix metalloproteinases [12] or vascular endothelial growth factor [2, 28]) or inhibit (e.g., thrombospondin [48] or tumstatin [23]) tumor growth. Extracellular matrix proteins, including fibronectin (FN) and its splice variants, are prominently expressed in and around tumors (10,32,47), but their roles in tumorigenesis are poorly understood. This study investigated the potential functions of FN splice variants, EIIIA and EIIIB, in physiological and tumor angiogenesis.FN is a large modular glycoprotein composed of type I, type II, and type III FN repeats and implicated in numerous cellular processes from cell migration to hemostasis (27, 39). FN-null embryos and embryoid bodies have very low numbers of endothelial cells and develop defective vessels (16, 18), and FNnull embryos die very early in utero from cardiovascular defects (18-20). These observations underscore the importance of FN in vascular development.FN RNA is alternatively spliced at three conserved regions, EIIIA (EDA), EIIIB (EDB), and V (CS-1). Although EIIIA and EIIIB sequences are only 29% identical within a species, interspecies comparisons show that amino acid sequences of EIIIB and EIIIA are highly conserved. For example, the mouse and human EIIIB and EIIIA segments are 100% and 96% identical, respectively. The patterns of expression of these splice variants are also conserved among species. In vivo, EIIIA and EIIIB FN splice variants are expressed around developing blood vessels during embryonic growth (14, 21, 44) when vessels are actively forming and being remodeled, but they are markedly downregulated in adult tiss...

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Section: Resultsmentioning

confidence: 99%

Direct Test of Potential Roles of EIIIA and EIIIB Alternatively Spliced Segments of Fibronectin in Physiological and Tumor Angiogenesis

Astrof

Crowley

George

et al. 2004

Molecular and Cellular Biology

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“…However, dogs treated with eplerenone also increased bFGF, which can promote angiogensis. [22][23][24][25] Thus, the increase in capillary density associated with eplerenone treatment may have been due in part to the upregulation of bFGF.…”

Section: Discussionmentioning

confidence: 99%

Effects of Long-Term Monotherapy With Eplerenone, a Novel Aldosterone Blocker, on Progression of Left Ventricular Dysfunction and Remodeling in Dogs With Heart Failure

et al. 2002

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Background-In heart failure (HF), aldosterone has been implicated in the formation of reactive interstitial fibrosis, a maladaptation that contributes to left ventricular (LV) remodeling. Eplerenone is a novel selective aldosterone blocker. The present study examined the effects of long-term monotherapy with eplerenone on the progression of LV dysfunction and remodeling in dogs with chronic HF. Methods and Results-HF was produced in 14 dogs by intracoronary microembolizations that were discontinued when LV ejection fraction (EF) was between 30% and 40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with eplerenone (10 mg/kg twice daily, nϭ7) or no therapy at all (control, nϭ7). Hemodynamic measurements were made just before randomization and were repeated at the end of 3 months of therapy. In control dogs, LV end-diastolic and end-systolic volume increased significantly (62Ϯ4 versus 68Ϯ4 mL, PϽ0.001, and 38Ϯ3 versus 47Ϯ3 mL, PϽ0.001, respectively), and EF decreased significantly (38Ϯ1% versus 31Ϯ2%, PϽ0.001). In contrast, end-diastolic volume, end-systolic volume, and EF remained unchanged during the 3 months of treatment in eplerenone-treated dogs. LV end-diastolic wall stress increased significantly in control dogs but decreased significantly in eplerenone-treated dogs. Compared with control, eplerenone was associated with a 28% reduction in cardiomyocyte cross-sectional area, a 37% reduction of volume fraction of reactive interstitial fibrosis, and a 34% reduction of volume fraction of replacement fibrosis. Conclusions-Our results indicate that long-term therapy with eplerenone prevents progressive LV dysfunction and attenuates LV remodeling in dogs with chronic HF.

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“…In other experiments, WT or HIV-Tg 26 adult male mice without preexisting renal disease were divided in two groups (n=3-5 mice per group) and injected through the retro-orbital vein plexus with adenoviral vectors carrying LacZ or a 700-bp cDNA sequence encoding a secreted form of human FGF-2 (rAd-FGF-2; 5310 8 pfu/mouse) as previously described. 38,69,70 Mice were euthanized 7 or 28 days after the adenoviral infection, and their kidneys were processed for signaling or renal histologic studies as described above. Renal injury was assessed in sections stained with period acid-Schiff by counting the percentage of glomeruli exhibiting segmental/global sclerosis and the percentage of tubular casts and microcysts.…”

Section: Studies In Wt and Hiv-tg 26 Micementioning

confidence: 99%

The Basic Domain of HIV-Tat Transactivating Protein Is Essential for Its Targeting to Lipid Rafts and Regulating Fibroblast Growth Factor-2 Signaling in Podocytes Isolated from Children with HIV-1–Associated Nephropathy

Xie¹,

Colberg-Poley

Das³

et al. 2014

Journal of the American Society of Nephrology

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Podocyte injury has a critical role in the pathogenesis of HIV-associated nephropathy (HIVAN). The HIV-1 transactivator of transcription (Tat), combined with fibroblast growth factor-2 (FGF-2), can induce the dedifferentiation and proliferation of cultured human podocytes. Cellular internalization of Tat requires interactions with heparan sulfate proteoglycans and cholesterol-enriched lipid rafts (LRs). However, the specific distribution of Tat in human podocytes and its ability to associate with LRs have not been documented. Here, we found that Tat is preferentially recruited to LRs in podocytes isolated from children with HIVAN. Furthermore, we identified arginines in the basic domain (RKKRRQRRR) of Tat as essential for (1) targeting Tat to LRs, (2) Tat-mediated increases in the expression of Rho-A and matrix metalloproteinase-9 in LRs, and (3) Tat-mediated enhancement of FGF-2 signaling in human podocytes and HIV-transgenic mouse kidneys and the exacerbation of renal lesions in these mice. Tat carrying alanine substitutions in the basic domain (AKKAAQAAA) remained localized in the cytosol and did not associate with LRs or enhance FGF-2 signaling in cultured podocytes. These results show the specific association of Tat with LRs in podocytes isolated from children with HIVAN, confirm Tat as a regulator of FGF-2 signaling in LRs, and identify the key domain of Tat responsible for promoting these effects and aggravating renal injury in HIV-transgenic mice. Moreover, these results provide a molecular framework for developing novel therapies to improve the clinical outcome of children with HIVAN.

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Strain-dependent anterior segment neovascularization following intravitreal gene transfer of basic fibroblast growth factor (bFGF)

Abstract: The low molecular weight form (18 kD) (but not the high molecular weight forms) of bFGF drives angiogenic response in the anterior segment of specific strains of mice. Genetic modifiers may contribute to and/or prevent neovascularization induced by bFGF.

Cited by 18 publications

References 22 publications

Direct Test of Potential Roles of EIIIA and EIIIB Alternatively Spliced Segments of Fibronectin in Physiological and Tumor Angiogenesis

Direct Test of Potential Roles of EIIIA and EIIIB Alternatively Spliced Segments of Fibronectin in Physiological and Tumor Angiogenesis

Effects of Long-Term Monotherapy With Eplerenone, a Novel Aldosterone Blocker, on Progression of Left Ventricular Dysfunction and Remodeling in Dogs With Heart Failure

The Basic Domain of HIV-Tat Transactivating Protein Is Essential for Its Targeting to Lipid Rafts and Regulating Fibroblast Growth Factor-2 Signaling in Podocytes Isolated from Children with HIV-1–Associated Nephropathy

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