Pharmacological targeting of vegfr signaling with axitinib inhibits tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis

Elena N. Atochina-Vasserman, Elena Abramova, Melane L. James, Ryan Rue, Amy Y. Liu, Nathan Tessema Ersumo, Chang Jiang Guo, Andrew J. Gow, Vera P. Krymskaya

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment, which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells, and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM.

Original languageEnglish
Pages (from-to)L1447-L1454
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume309
Issue number12
DOIs
Publication statusPublished - 2015
Externally publishedYes

Fingerprint

Lymphangioleiomyomatosis
Tuberous Sclerosis
Vascular Endothelial Growth Factor D
Pharmacology
Lung
Growth
Vascular Endothelial Growth Factor Receptor
Up-Regulation
Serum
axitinib
Tuberous Sclerosis 2
United States Food and Drug Administration
Tumor Suppressor Genes
Respiratory Insufficiency
Lung Diseases
Nitric Oxide
Mutation

Keywords

  • Animal models
  • Axitinib
  • Lymphangiogenesis
  • TCS2-null
  • VEGF-D

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

Cite this

Pharmacological targeting of vegfr signaling with axitinib inhibits tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis. / Atochina-Vasserman, Elena N.; Abramova, Elena; James, Melane L.; Rue, Ryan; Liu, Amy Y.; Ersumo, Nathan Tessema; Guo, Chang Jiang; Gow, Andrew J.; Krymskaya, Vera P.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 309, No. 12, 2015, p. L1447-L1454.

Research output: Contribution to journalArticle

Atochina-Vasserman, Elena N. ; Abramova, Elena ; James, Melane L. ; Rue, Ryan ; Liu, Amy Y. ; Ersumo, Nathan Tessema ; Guo, Chang Jiang ; Gow, Andrew J. ; Krymskaya, Vera P. / Pharmacological targeting of vegfr signaling with axitinib inhibits tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2015 ; Vol. 309, No. 12. pp. L1447-L1454.
@article{84ecbc9243cf458fb84ba425c5052fe9,
title = "Pharmacological targeting of vegfr signaling with axitinib inhibits tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis",
abstract = "Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment, which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells, and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM.",
keywords = "Animal models, Axitinib, Lymphangiogenesis, TCS2-null, VEGF-D",
author = "Atochina-Vasserman, {Elena N.} and Elena Abramova and James, {Melane L.} and Ryan Rue and Liu, {Amy Y.} and Ersumo, {Nathan Tessema} and Guo, {Chang Jiang} and Gow, {Andrew J.} and Krymskaya, {Vera P.}",
year = "2015",
doi = "10.1152/ajplung.00262.2015.",
language = "English",
volume = "309",
pages = "L1447--L1454",
journal = "American Journal of Physiology - Lung Cellular and Molecular Physiology",
issn = "1040-0605",
publisher = "American Physiological Society",
number = "12",

}

TY - JOUR

T1 - Pharmacological targeting of vegfr signaling with axitinib inhibits tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis

AU - Atochina-Vasserman, Elena N.

AU - Abramova, Elena

AU - James, Melane L.

AU - Rue, Ryan

AU - Liu, Amy Y.

AU - Ersumo, Nathan Tessema

AU - Guo, Chang Jiang

AU - Gow, Andrew J.

AU - Krymskaya, Vera P.

PY - 2015

Y1 - 2015

N2 - Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment, which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells, and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM.

AB - Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment, which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells, and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM.

KW - Animal models

KW - Axitinib

KW - Lymphangiogenesis

KW - TCS2-null

KW - VEGF-D

UR - http://www.scopus.com/inward/record.url?scp=84951131509&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84951131509&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00262.2015.

DO - 10.1152/ajplung.00262.2015.

M3 - Article

VL - 309

SP - L1447-L1454

JO - American Journal of Physiology - Lung Cellular and Molecular Physiology

JF - American Journal of Physiology - Lung Cellular and Molecular Physiology

SN - 1040-0605

IS - 12

ER -