Vascular Endothelial Growth Factor (VEGF)-D Stimulates VEGF-A, Stanniocalcin-1, and Neuropilin-2 and Has Potent Angiogenic Effects

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 31; no. 7; pp. 1617 - 1624
• Main Authors: Jauhiainen, Suvi, Häkkinen, Sanna-Kaisa, Toivanen, Pyry I, Heinonen, Suvi E, Jyrkkänen, Henna-Kaisa, Kansanen, Emilia, Leinonen, Hanna, Levonen, Anna-Liisa, Ylä-Herttuala, Seppo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.07.2011; Lippincott Williams & Wilkins
• Subjects: Animals; Apolipoprotein B-100 - deficiency; Apolipoprotein B-100 - genetics; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Blotting, Western; Cardiology. Vascular system; Cell Proliferation; Cells, Cultured; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Glycoproteins - metabolism; Hindlimb; Humans; Medical sciences; Mice; Mice, Knockout; Muscle, Skeletal - blood supply; Neovascularization, Physiologic; Neuropilin-1 - metabolism; Neuropilin-2 - genetics; Neuropilin-2 - metabolism; Nitric Oxide Synthase Type III - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Receptors, LDL - deficiency; Receptors, LDL - genetics; Recombinant Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Time Factors; Transduction, Genetic; Up-Regulation; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor D - genetics; Vascular Endothelial Growth Factor D - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vertebrates: cardiovascular system; Vascular disease; Angiogenesis; growth factors; Atherosclerosis; Cardiovascular disease; vascular biology; Gene expression; Endothelium; Growth factor
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.111.225961

OBJECTIVE—The mature form of human vascular endothelial growth factor-D (hVEGF-D) is an efficient angiogenic factor, but its full mechanism of action has remained unclear. We studied the effects of hVEGF-D in endothelial cells using gene array, signaling, cell culture, and in vivo gene transfer techniques. METHODS AND RESULTS—Concomitant with the angiogenic and proliferative responses, hVEGF-D enhanced the phosphorylation of VEGF receptor-2, Akt, and endothelial nitric oxide synthase. Gene arrays, quantitative reverse transcription–polymerase chain reaction, and Western blot revealed increases in VEGF-A, stanniocalcin-1 (STC1), and neuropilin (NRP) 2 expression by hVEGF-D stimulation, whereas induction with hVEGF-A165 altered the expression of STC1 and NRP1, another coreceptor for VEGFs. The effects of hVEGF-D were seen only under high-serum conditions, whereas for hVEGF-A165, the strongest response was observed under low-serum conditions. The hVEGF-D-induced upregulation of STC1 and NRP2 was also evident in vivo in mouse skeletal muscle treated with hVEGF-D by adenoviral gene delivery. The importance of NRP2 in hVEGF-D signaling was further studied with NRP2 small interfering RNA and NRP antagonist, which were able to block hVEGF-D-induced survival of endothelial cells. CONCLUSION—In this study, the importance of serum and upregulation of NRP2 and STC1 for VEGF-D effects were demonstrated. Better knowledge of VEGF-D signaling and regulation is valuable for the development of efficient and safe VEGF-D-based therapeutic applications for cardiovascular diseases.