Hypoxia effects on proangiogenic factors in human umbilical vein endothelial cells: functional role of the peptide somatostatin

Massimo Dal Monte, Davide Martini, Chiara Ristori, Danilo Azara, Chiara Armani, Alberto Balbarini, Paola Bagnoli
Naunyn-Schmiedeberg's Archives of Pharmacology 2011, 383 (6): 593-612
The aim of this study was to investigate hypoxia effects on vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2 in human umbilical vein endothelial cells (HUVEC) and to determine their modulation by the peptide somatostatin (SRIF) and its analogues. The involvement of signal transducer and activator of transcription (STAT) 3 and hypoxia inducible factor (HIF)-1 was also investigated. Quantitative real-time PCR, Western blot and ELISA were used. Hypoxia upregulated VEGF expression and release, whereas it downregulated VEGFR-1 and VEGFR-2. In contrast, neither the expression nor the phosphorylation of the platelet-derived growth factor receptor (PDGFR) β was affected by hypoxia. SU1498 at 1 μM did not affect pVEGFR-2 and pPDGFRβ, whereas at 20 μM it inhibited pVEGFR-2, but not pPDGFRβ. Upregulated VEGF expression and release were prevented by SU1498, which also inhibited the hypoxia-induced pSTAT3 and HIF-1α. Blocking pSTAT3 with S3I-201 inhibited HIF-1α and VEGF upregulation, suggesting the existence of an autocrine loop involving STAT3, HIF-1, VEGF and VEGFR-2. Endothelial cells express somatostatin (SRIF) receptors (sst(1-5)) although less is known in HUVEC. We found that sst(1) and sst(4) were expressed by HUVEC with sst(1) more expressed than sst(4) mRNA. Hypoxia downregulated sst(1), whereas it upregulated sst(4). The sst(1) downregulation, but not the sst(4) upregulation, was prevented by SU1498, S3I-201 or YC-1, an inhibitor of HIF-1α. SRIF and the sst(1) agonist CH-275, but not the sst(4) agonist L803,087 and the sst(2)/sst(3)/sst(5) agonist octreotide, prevented hypoxia effects on VEGF and its receptors. In addition, SRIF and CH-275 inhibited the hypoxia-induced pSTAT3 and HIF-1α accumulation. Our results suggest that SRIF acting at sst(1) limits upregulated VEGF expression and release through a control on the activity of STAT3 and HIF-1, supporting the possible use of sst(1) agonists in antiangiogenic therapies.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"