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Induction of the angiogenic phenotype by Hox D3.

Boudreau N, Andrews C, Srebrow A, Ravanpay A, Cheresh DA - J. Cell Biol. (1997)

Bottom Line: Expression of Hox D3, in the absence of bFGF, resulted in enhanced expression of integrin alphavbeta3 and uPA.In fact, sustained expression of Hox D3 in vivo on the chick chorioallantoic membrane retained EC in this invasive state and prevented vessel maturation leading to vascular malformations and endotheliomas.Therefore, Hox D3 regulates EC gene expression associated with the invasive stage of angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, USA. nboudrea@nsc.vcu.edu

ABSTRACT
Angiogenesis is characterized by distinct phenotypic changes in vascular endothelial cells (EC). Evidence is provided that the Hox D3 homeobox gene mediates conversion of endothelium from the resting to the angiogenic/invasive state. Stimulation of EC with basic fibroblast growth factor (bFGF) resulted in increased expression of Hox D3, integrin alphavbeta3, and the urokinase plasminogen activator (uPA). Hox D3 antisense blocked the ability of bFGF to induce uPA and integrin alphavbeta3 expression, yet had no effect on EC cell proliferation or bFGF-mediated cyclin D1 expression. Expression of Hox D3, in the absence of bFGF, resulted in enhanced expression of integrin alphavbeta3 and uPA. In fact, sustained expression of Hox D3 in vivo on the chick chorioallantoic membrane retained EC in this invasive state and prevented vessel maturation leading to vascular malformations and endotheliomas. Therefore, Hox D3 regulates EC gene expression associated with the invasive stage of angiogenesis.

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Effect of retroviral-mediated expression  of Hox D3 in chick embryos. (A and B) Morphology of tumors generated 3 d after grafting of QT6  cells producing control or Hox D3-expressing retrovirus onto 10 d chick CAMs. (C and D) H&E  staining in tissue cross-sections from tumors (t)  and vasculature produced by cells shedding control or Hox D3-expressing retrovirus. Note the  large hemorrhagic region containing hematopoietic cells (h) adjacent to tumor tissue in the Hox  D3-infected tissue. Bar, 50 μm.
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Figure 6: Effect of retroviral-mediated expression of Hox D3 in chick embryos. (A and B) Morphology of tumors generated 3 d after grafting of QT6 cells producing control or Hox D3-expressing retrovirus onto 10 d chick CAMs. (C and D) H&E staining in tissue cross-sections from tumors (t) and vasculature produced by cells shedding control or Hox D3-expressing retrovirus. Note the large hemorrhagic region containing hematopoietic cells (h) adjacent to tumor tissue in the Hox D3-infected tissue. Bar, 50 μm.

Mentions: These vascular malformations or endotheliomas ultimately resulted in the formation of large hemorrhagic zones within the tumors generated by 15/18 Hox D3-infected embryos, but was not observed in tumors of the control embryos (Fig. 6, A and B). H&E staining of sectioned Hox D3-infected tissue showed large endothelial-lined cysts filled with hematopoietic cells, many of which had hemorrhaged (Fig. 6 D). In contrast, tumors producing control virus showed normal tumor-induced angiogenesis (Fig. 6 C). These findings not only establish a role for Hox D3 in EC function but also emphasize the requirement for tightly regulated expression of Hox D3 during the early events of angiogenesis.


Induction of the angiogenic phenotype by Hox D3.

Boudreau N, Andrews C, Srebrow A, Ravanpay A, Cheresh DA - J. Cell Biol. (1997)

Effect of retroviral-mediated expression  of Hox D3 in chick embryos. (A and B) Morphology of tumors generated 3 d after grafting of QT6  cells producing control or Hox D3-expressing retrovirus onto 10 d chick CAMs. (C and D) H&E  staining in tissue cross-sections from tumors (t)  and vasculature produced by cells shedding control or Hox D3-expressing retrovirus. Note the  large hemorrhagic region containing hematopoietic cells (h) adjacent to tumor tissue in the Hox  D3-infected tissue. Bar, 50 μm.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2139816&req=5

Figure 6: Effect of retroviral-mediated expression of Hox D3 in chick embryos. (A and B) Morphology of tumors generated 3 d after grafting of QT6 cells producing control or Hox D3-expressing retrovirus onto 10 d chick CAMs. (C and D) H&E staining in tissue cross-sections from tumors (t) and vasculature produced by cells shedding control or Hox D3-expressing retrovirus. Note the large hemorrhagic region containing hematopoietic cells (h) adjacent to tumor tissue in the Hox D3-infected tissue. Bar, 50 μm.
Mentions: These vascular malformations or endotheliomas ultimately resulted in the formation of large hemorrhagic zones within the tumors generated by 15/18 Hox D3-infected embryos, but was not observed in tumors of the control embryos (Fig. 6, A and B). H&E staining of sectioned Hox D3-infected tissue showed large endothelial-lined cysts filled with hematopoietic cells, many of which had hemorrhaged (Fig. 6 D). In contrast, tumors producing control virus showed normal tumor-induced angiogenesis (Fig. 6 C). These findings not only establish a role for Hox D3 in EC function but also emphasize the requirement for tightly regulated expression of Hox D3 during the early events of angiogenesis.

Bottom Line: Expression of Hox D3, in the absence of bFGF, resulted in enhanced expression of integrin alphavbeta3 and uPA.In fact, sustained expression of Hox D3 in vivo on the chick chorioallantoic membrane retained EC in this invasive state and prevented vessel maturation leading to vascular malformations and endotheliomas.Therefore, Hox D3 regulates EC gene expression associated with the invasive stage of angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, USA. nboudrea@nsc.vcu.edu

ABSTRACT
Angiogenesis is characterized by distinct phenotypic changes in vascular endothelial cells (EC). Evidence is provided that the Hox D3 homeobox gene mediates conversion of endothelium from the resting to the angiogenic/invasive state. Stimulation of EC with basic fibroblast growth factor (bFGF) resulted in increased expression of Hox D3, integrin alphavbeta3, and the urokinase plasminogen activator (uPA). Hox D3 antisense blocked the ability of bFGF to induce uPA and integrin alphavbeta3 expression, yet had no effect on EC cell proliferation or bFGF-mediated cyclin D1 expression. Expression of Hox D3, in the absence of bFGF, resulted in enhanced expression of integrin alphavbeta3 and uPA. In fact, sustained expression of Hox D3 in vivo on the chick chorioallantoic membrane retained EC in this invasive state and prevented vessel maturation leading to vascular malformations and endotheliomas. Therefore, Hox D3 regulates EC gene expression associated with the invasive stage of angiogenesis.

Show MeSH
Related in: MedlinePlus