Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 299 (5608): 890-893

Copyright © 2003 by the American Association for the Advancement of Science

Angiogenesis-Independent Endothelial Protection of Liver: Role of VEGFR-1

Jennifer LeCouter,1 Dirk R. Moritz,1* Bing Li,2 Gail Lewis Phillips,1 Xiao Huan Liang,1 Hans-Peter Gerber,1 Kenneth J. Hillan,3 Napoleone Ferrara1dagger

The vascular endothelium was once thought to function primarily in nutrient and oxygen delivery, but recent evidence suggests that it may play a broader role in tissue homeostasis. To explore the role of sinusoidal endothelial cells (LSECs) in the adult liver, we studied the effects of vascular endothelial growth factor (VEGF) receptor activation on mouse hepatocyte growth. Delivery of VEGF-A increased liver mass in mice but did not stimulate growth of hepatocytes in vitro, unless LSECs were also present in the culture. Hepatocyte growth factor (HGF) was identified as one of the LSEC-derived paracrine mediators promoting hepatocyte growth. Selective activation of VEGF receptor-1 (VEGFR-1) stimulated hepatocyte but not endothelial proliferation in vivo and reduced liver damage in mice exposed to a hepatotoxin. Thus, VEGFR-1 agonists may have therapeutic potential for preservation of organ function in certain liver disorders.

Departments of 1 Molecular Oncology, 2 Protein Engineering, and 3 Pathology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
*   Present address: Amgen, Alpenquai 30, Post Office Box 2065, CH-6002 Lucerne, Switzerland.

dagger    To whom correspondence should be addressed. E-mail: nf{at}gene.com

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Phosphoproteomic Analysis Implicates the mTORC2-FoxO1 Axis in VEGF Signaling and Feedback Activation of Receptor Tyrosine Kinases.
G. Zhuang, K. Yu, Z. Jiang, A. Chung, J. Yao, C. Ha, K. Toy, R. Soriano, B. Haley, E. Blackwood, et al. (2013)
Science Signaling 6, ra25
   Abstract »    Full Text »    PDF »
Gender and strain-specific differences in the development of steatosis in rats.
S. Stoppeler, D. Palmes, M. Fehr, J. P. Holzen, A. Zibert, R. Siaj, H. H.-J. Schmidt, H.-U. Spiegel, and R. Bahde (2013)
Laboratory Animals 47, 43-52
   Abstract »    Full Text »    PDF »
Bevacizumab Impairs Hepatocyte Proliferation after Partial Hepatectomy in a Rabbit Model.
A. DUPRE, A. PARADISI, S. LANGONNET, A. GANDINI, P. MEHLEN, and M. RIVOIRE (2012)
Anticancer Res 32, 5193-5200
   Abstract »    Full Text »    PDF »
Vascular instruction of pancreas development.
O. Cleaver and Y. Dor (2012)
Development 139, 2833-2843
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor and Vascular Homeostasis.
A. Lazarus and E. Keshet (2011)
8, 508-511
   Abstract »    Full Text »    PDF »
Blood vessels restrain pancreas branching, differentiation and growth.
J. Magenheim, O. Ilovich, A. Lazarus, A. Klochendler, O. Ziv, R. Werman, A. Hija, O. Cleaver, E. Mishani, E. Keshet, et al. (2011)
Development 138, 4743-4752
   Abstract »    Full Text »    PDF »
Expression of a functional VEGFR-1 in tumor cells is a major determinant of anti-PlGF antibodies efficacy.
J. Yao, X. Wu, G. Zhuang, I. M. Kasman, T. Vogt, V. Phan, M. Shibuya, N. Ferrara, and C. Bais (2011)
PNAS 108, 11590-11595
   Abstract »    Full Text »    PDF »
Thrombospondin-1: An Islet Endothelial Cell Signal of Importance for {beta}-Cell Function.
J. Olerud, D. Mokhtari, M. Johansson, G. Christoffersson, J. Lawler, N. Welsh, and P.-O. Carlsson (2011)
Diabetes 60, 1946-1954
   Abstract »    Full Text »    PDF »
Preeclampsia, a Disease of the Maternal Endothelium: The Role of Antiangiogenic Factors and Implications for Later Cardiovascular Disease.
C. E. Powe, R. J. Levine, and S. A. Karumanchi (2011)
Circulation 123, 2856-2869
   Full Text »    PDF »
Vascular Endothelial Growth Factor Receptor-1 Signaling Promotes Liver Repair through Restoration of Liver Microvasculature after Acetaminophen Hepatotoxicity.
T. Kato, Y. Ito, K. Hosono, T. Suzuki, H. Tamaki, T. Minamino, S. Kato, H. Sakagami, M. Shibuya, and M. Majima (2011)
Toxicol. Sci. 120, 218-229
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor Receptor-1 Signaling Promotes Mobilization of Macrophage Lineage Cells from Bone Marrow and Stimulates Solid Tumor Growth.
M. Muramatsu, S. Yamamoto, T. Osawa, and M. Shibuya (2010)
Cancer Res. 70, 8211-8221
   Abstract »    Full Text »    PDF »
Human Recombinant Vascular Endothelial Growth Factor Reduces Necrosis and Enhances Hepatocyte Regeneration in a Mouse Model of Acetaminophen Toxicity.
B. C. Donahower, S. S. McCullough, L. Hennings, P. M. Simpson, C. D. Stowe, A. G. Saad, R. C. Kurten, J. A. Hinson, and L. P. James (2010)
J. Pharmacol. Exp. Ther. 334, 33-43
   Abstract »    Full Text »    PDF »
Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration.
S. Hoehme, M. Brulport, A. Bauer, E. Bedawy, W. Schormann, M. Hermes, V. Puppe, R. Gebhardt, S. Zellmer, M. Schwarz, et al. (2010)
PNAS 107, 10371-10376
   Abstract »    Full Text »    PDF »
Cardiomyocyte VEGFR-1 activation by VEGF-B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction.
L. Zentilin, U. Puligadda, V. Lionetti, S. Zacchigna, C. Collesi, L. Pattarini, G. Ruozi, S. Camporesi, G. Sinagra, M. Pepe, et al. (2010)
FASEB J 24, 1467-1478
   Abstract »    Full Text »    PDF »
Vascular endothelial growth factor regulates germ cell survival during establishment of spermatogenesis in the bovine testis.
K. C Caires, J. de Avila, and D. J McLean (2009)
Reproduction 138, 667-677
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor (VEGF) Receptor-2 Tyrosine 1175 Signaling Controls VEGF-induced von Willebrand Factor Release from Endothelial Cells via Phospholipase C-{gamma}1- and Protein Kinase A-dependent Pathways.
Y. Xiong, Y. Huo, C. Chen, H. Zeng, X. Lu, C. Wei, C. Ruan, X. Zhang, Z. Hu, M. Shibuya, et al. (2009)
J. Biol. Chem. 284, 23217-23224
   Abstract »    Full Text »    PDF »
Human Hepatocellular Carcinoma Tumor-derived Endothelial Cells Manifest Increased Angiogenesis Capability and Drug Resistance Compared with Normal Endothelial Cells.
Y.-Q. Xiong, H.-C. Sun, W. Zhang, X.-D. Zhu, P.-Y. Zhuang, J.-B. Zhang, L. Wang, W.-z. Wu, L.-X. Qin, and Z.-Y. Tang (2009)
Clin. Cancer Res. 15, 4838-4846
   Abstract »    Full Text »    PDF »
Amino acid-mediated heterotypic interaction governs performance of a hepatic tissue model.
R. Jindal, Y. Nahmias, A. W. Tilles, F. Berthiaume, and M. L. Yarmush (2009)
FASEB J 23, 2288-2298
   Abstract »    Full Text »    PDF »
Generation and Regeneration of Cells of the Liver and Pancreas.
K. S. Zaret and M. Grompe (2008)
Science 322, 1490-1494
   Abstract »    Full Text »    PDF »
Pegaptanib sodium for neovascular age-related macular degeneration: third-year safety results of the VEGF Inhibition Study in Ocular Neovascularisation (VISION) trial.
L J Singerman, H Masonson, M Patel, A P Adamis, R Buggage, E Cunningham, M Goldbaum, B Katz, and D Guyer (2008)
Br J Ophthalmol 92, 1606-1611
   Abstract »    Full Text »    PDF »
Focal Gains of VEGFA and Molecular Classification of Hepatocellular Carcinoma.
D. Y. Chiang, A. Villanueva, Y. Hoshida, J. Peix, P. Newell, B. Minguez, A. C. LeBlanc, D. J. Donovan, S. N. Thung, M. Sole, et al. (2008)
Cancer Res. 68, 6779-6788
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor Signaling Pathways: Therapeutic Perspective.
M. Kowanetz and N. Ferrara (2008)
Am. Assoc. Cancer Res. Educ. Book 2008, 173-181
   Abstract »    Full Text »    PDF »
Effect of Molecular Therapeutics on Liver Regeneration in a Murine Model.
G. Van Buren II, A. D. Yang, N. A. Dallas, M. J. Gray, S. J. Lim, L. Xia, F. Fan, R. Somcio, Y. Wu, D. J. Hicklin, et al. (2008)
J. Clin. Oncol. 26, 1836-1842
   Abstract »    Full Text »    PDF »
Regulation of Vasculogenesis by Platelet-Mediated Recruitment of Bone Marrow-Derived Cells.
D. C. Rafii, B. Psaila, J. Butler, D. K. Jin, and D. Lyden (2008)
Arterioscler Thromb Vasc Biol 28, 217-222
   Abstract »    Full Text »    PDF »
Rat liver sinusoidal endothelial cells survive without exogenous VEGF in 3D perfused co-cultures with hepatocytes.
A. J. Hwa, R. C. Fry, A. Sivaraman, P. T. So, L. D. Samson, D. B. Stolz, and L. G. Griffith (2007)
FASEB J 21, 2564-2579
   Abstract »    Full Text »    PDF »
Quantitative liver functions in Turner syndrome with and without hormone replacement therapy.
C. H. Gravholt, H. E. Poulsen, P. Ott, J. S. Christiansen, and H. Vilstrup (2007)
Eur. J. Endocrinol. 156, 679-686
   Abstract »    Full Text »    PDF »
Des-{gamma}-carboxyl Prothrombin-promoted Vascular Endothelial Cell Proliferation and Migration.
T. Fujikawa, H. Shiraha, N. Ueda, N. Takaoka, Y. Nakanishi, N. Matsuo, S. Tanaka, S.-i. Nishina, M. Suzuki, A. Takaki, et al. (2007)
J. Biol. Chem. 282, 8741-8748
   Abstract »    Full Text »    PDF »
Phenotypic Heterogeneity of the Endothelium: II. Representative Vascular Beds.
W. C. Aird (2007)
Circ. Res. 100, 174-190
   Abstract »    Full Text »    PDF »
Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade.
W. Wu, A. Onn, T. Isobe, S. Itasaka, R. R. Langley, T. Shitani, K. Shibuya, R. Komaki, A. J. Ryan, I. J. Fidler, et al. (2007)
Mol. Cancer Ther. 6, 471-483
   Abstract »    Full Text »    PDF »
Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway.
I. Shiojima and K. Walsh (2006)
Genes & Dev. 20, 3347-3365
   Abstract »    Full Text »    PDF »
Preparing the "Soil": The Premetastatic Niche.
R. N. Kaplan, S. Rafii, and D. Lyden (2006)
Cancer Res. 66, 11089-11093
   Abstract »    Full Text »    PDF »
Hypoxia-Independent Overexpression of Hypoxia-Inducible Factor 1{alpha} as an Early Change in Mouse Hepatocarcinogenesis.
H. Tanaka, M. Yamamoto, N. Hashimoto, M. Miyakoshi, S. Tamakawa, M. Yoshie, Y. Tokusashi, K. Yokoyama, Y. Yaginuma, and K. Ogawa (2006)
Cancer Res. 66, 11263-11270
   Abstract »    Full Text »    PDF »
Rat liver endothelial cells isolated by anti-CD31 immunomagnetic separation lack fenestrae and sieve plates.
L. D. DeLeve, X. Wang, M. K. McCuskey, and R. S. McCuskey (2006)
Am J Physiol Gastrointest Liver Physiol 291, G1187-G1189
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor Signaling Pathways: Therapeutic Perspective.
M. Kowanetz and N. Ferrara (2006)
Clin. Cancer Res. 12, 5018-5022
   Abstract »    Full Text »    PDF »
Hepatocyte growth factor mediates angiopoietin-induced smooth muscle cell recruitment.
H. Kobayashi, L. M. DeBusk, Y. O. Babichev, D. J. Dumont, and P. C. Lin (2006)
Blood 108, 1260-1266
   Abstract »    Full Text »    PDF »
Administration of r-VEGF-A prevents hepatic artery ligation-induced bile duct damage in bile duct ligated rats.
E. Gaudio, B. Barbaro, D. Alvaro, S. Glaser, H. Francis, A. Franchitto, P. Onori, Y. Ueno, M. Marzioni, G. Fava, et al. (2006)
Am J Physiol Gastrointest Liver Physiol 291, G307-G317
   Abstract »    Full Text »    PDF »
Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity.
B. Donahower, S. S. McCullough, R. Kurten, L. W. Lamps, P. Simpson, J. A. Hinson, and L. P. James (2006)
Am J Physiol Gastrointest Liver Physiol 291, G102-G109
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor-D Activates VEGFR-3 Expressed in Osteoblasts Inducing Their Differentiation.
M. Orlandini, A. Spreafico, M. Bardelli, M. Rocchigiani, A. Salameh, S. Nucciotti, C. Capperucci, B. Frediani, and S. Oliviero (2006)
J. Biol. Chem. 281, 17961-17967
   Abstract »    Full Text »    PDF »
Altered Expression of Endothelin, Vascular Endothelial Growth Factor, and Its Receptor in Hepatic Tissue in Endotoxemic Rat.
S. Zaedi, S. Jesmin, N. Yamaguchi, N. Shimojo, S. Maeda, S. Gando, I. Yamaguchi, K. Goto, and T. Miyauchi (2006)
Exp Biol Med 231, 1182-1186
   Abstract »    Full Text »    PDF »
Islet Endothelial Cells and Pancreatic {beta}-Cell Proliferation: Studies in Vitro and during Pregnancy in Adult Rats.
M. Johansson, G. Mattsson, A. Andersson, L. Jansson, and P.-O. Carlsson (2006)
Endocrinology 147, 2315-2324
   Abstract »    Full Text »    PDF »
Adeno-Associated Virus-Mediated Transduction of VEGF165 Improves Cardiac Tissue Viability and Functional Recovery After Permanent Coronary Occlusion in Conscious Dogs.
M. Ferrarini, N. Arsic, F. A. Recchia, L. Zentilin, S. Zacchigna, X. Xu, A. Linke, M. Giacca, and T. H. Hintze (2006)
Circ. Res. 98, 954-961
   Abstract »    Full Text »    PDF »
A Single Amino Acid Substitution in the Activation Loop Defines the Decoy Characteristic of VEGFR-1/FLT-1.
R. D. Meyer, M. Mohammadi, and N. Rahimi (2006)
J. Biol. Chem. 281, 867-875
   Abstract »    Full Text »    PDF »
Non-parenchymal liver cells support the growth advantage in the first stages of hepatocarcinogenesis.
C. Drucker, W. Parzefall, O. Teufelhofer, M. Grusch, A. Ellinger, R. Schulte-Hermann, and B. Grasl-Kraupp (2006)
Carcinogenesis 27, 152-161
   Abstract »    Full Text »    PDF »
Surgical Resection After Downsizing of Colorectal Liver Metastasis in the Era of Bevacizumab.
L. M. Ellis, S. A. Curley, and A. Grothey (2005)
J. Clin. Oncol. 23, 4853-4855
   Full Text »    PDF »
VEGF is crucial for the hepatic vascular development required for lipoprotein uptake.
B. Carpenter, Y. Lin, S. Stoll, R. L. Raffai, R. McCuskey, and R. Wang (2005)
Development 132, 3293-3303
   Abstract »    Full Text »    PDF »
Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice.
T. R. Carlson, Y. Yan, X. Wu, M. T. Lam, G. L. Tang, L. J. Beverly, L. M. Messina, A. J. Capobianco, Z. Werb, and R. Wang (2005)
PNAS 102, 9884-9889
   Abstract »    Full Text »    PDF »
Placenta growth factor expression is correlated with survival of patients with colorectal cancer.
S-C Wei, P-N Tsao, S-C Yu, C-T Shun, J-J Tsai-Wu, C H H Wu, Y-N Su, F-J Hsieh, and J-M Wong (2005)
Gut 54, 666-672
   Abstract »    Full Text »    PDF »
Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction.
G. Belteki, J. Haigh, N. Kabacs, K. Haigh, K. Sison, F. Costantini, J. Whitsett, S. E. Quaggin, and A. Nagy (2005)
Nucleic Acids Res. 33, e51
   Abstract »    Full Text »    PDF »
Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma.
J. S. Campbell, S. D. Hughes, D. G. Gilbertson, T. E. Palmer, M. S. Holdren, A. C. Haran, M. M. Odell, R. L. Bauer, H.-P. Ren, H. S. Haugen, et al. (2005)
PNAS 102, 3389-3394
   Abstract »    Full Text »    PDF »
The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications.
K. Podar and K. C. Anderson (2005)
Blood 105, 1383-1395
   Abstract »    Full Text »    PDF »
Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis.
D. J. Hicklin and L. M. Ellis (2005)
J. Clin. Oncol. 23, 1011-1027
   Abstract »    Full Text »    PDF »
Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization.
J. LeCouter, C. Zlot, M. Tejada, F. Peale, and N. Ferrara (2004)
PNAS 101, 16813-16818
   Abstract »    Full Text »    PDF »
Vascular endothelial growth factor receptor-3 in hypoxia-induced vascular development.
I. NILSSON, C. ROLNY, Y. WU, B. PYTOWSKI, D. HICKLIN, K. ALITALO, L. CLAESSON-WELSH, and S. WENNSTROM (2004)
FASEB J 18, 1507-1515
   Abstract »    Full Text »    PDF »
Rat liver sinusoidal endothelial cell phenotype is maintained by paracrine and autocrine regulation.
L. D. DeLeve, X. Wang, L. Hu, M. K. McCuskey, and R. S. McCuskey (2004)
Am J Physiol Gastrointest Liver Physiol 287, G757-G763
   Abstract »    Full Text »    PDF »
Decay-accelerating Factor Induction on Vascular Endothelium by Vascular Endothelial Growth Factor (VEGF) Is Mediated via a VEGF Receptor-2 (VEGF-R2)- and Protein Kinase C-{alpha}/{epsilon} (PKC{alpha}/{epsilon})-dependent Cytoprotective Signaling Pathway and Is Inhibited by Cyclosporin A.
J. C. Mason, R. Steinberg, E. A. Lidington, A. R. Kinderlerer, M. Ohba, and D. O. Haskard (2004)
J. Biol. Chem. 279, 41611-41618
   Abstract »    Full Text »    PDF »
Dual Hormonal Regulation of Endocrine Tissue Mass and Vasculature by Adrenocorticotropin in the Adrenal Cortex.
M. Thomas, M. Keramidas, E. Monchaux, and J.-J. Feige (2004)
Endocrinology 145, 4320-4329
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor: Basic Science and Clinical Progress.
N. Ferrara (2004)
Endocr. Rev. 25, 581-611
   Abstract »    Full Text »    PDF »
Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells.
B. A. Hesser, X. H. Liang, G. Camenisch, S. Yang, D. A. Lewin, R. Scheller, N. Ferrara, and H.-P. Gerber (2004)
Blood 104, 149-158
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor and Its Receptor, Flk-1/KDR, Are Cytoprotective in the Extravascular Compartment of the Ovarian Follicle.
J. Greenaway, K. Connor, H. G. Pedersen, B. L. Coomber, J. LaMarre, and J. Petrik (2004)
Endocrinology 145, 2896-2905
   Abstract »    Full Text »    PDF »
Plasticity of endothelial cells: rapid dedifferentiation of freshly isolated high endothelial venule endothelial cells outside the lymphoid tissue microenvironment.
D.-A. Lacorre, E. S. Baekkevold, I. Garrido, P. Brandtzaeg, G. Haraldsen, F. Amalric, and J.-P. Girard (2004)
Blood 103, 4164-4172
   Abstract »    Full Text »    PDF »
Overexpression of Placenta Growth Factor Contributes to the Pathogenesis of Pulmonary Emphysema.
P.-N. Tsao, Y.-N. Su, H. Li, P.-H. Huang, C.-T. Chien, Y.-L. Lai, C.-N. Lee, C.-A. Chen, W.-F. Cheng, S.-C. Wei, et al. (2004)
169, 505-511
   Abstract »    Full Text »    PDF »
Paracrine Regulation of Angiogenesis and Adipocyte Differentiation During In Vivo Adipogenesis.
D. Fukumura, A. Ushiyama, D. G. Duda, L. Xu, J. Tam, V. Krishna, K. Chatterjee, I. Garkavtsev, and R. K. Jain (2003)
Circ. Res. 93, e88-e97
   Abstract »    Full Text »    PDF »
The transcription factor Net regulates the angiogenic switch.
H. Zheng, C. Wasylyk, A. Ayadi, J. Abecassis, J. A Schalken, H. Rogatsch, N. Wernert, S.-M. Maira, M.-C. Multon, and B. Wasylyk (2003)
Genes & Dev. 17, 2283-2297
   Abstract »    Full Text »    PDF »
Mouse Endocrine Gland-Derived Vascular Endothelial Growth Factor: A Distinct Expression Pattern from Its Human Ortholog Suggests Different Roles as a Regulator of Organ-Specific Angiogenesis.
J. LeCouter, R. Lin, G. Frantz, Z. Zhang, K. Hillan, and N. Ferrara (2003)
Endocrinology 144, 2606-2616
   Abstract »    Full Text »    PDF »
BIOMEDICINE: Love, Honor, and Protect (Your Liver).
A. J. Davidson and L. I. Zon (2003)
Science 299, 835-837
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882