J Korean Diabetes Assoc.  2002 Oct;26(5):396-404.

Effect and Mechanism of Vascular Endothelial Growth Factor on Endothelial Nitric Oxide Synthase Expression in Aortic Endothelial Cells

• Lee SH
• Kim JG
• Park JY
• Ha SW
• Kim BW

Abstract

BACKGROUND: Vascular endothelial growth factor (VEGF), a soluble angiogenic factor produced by many tumor and normal cells, is a potent angiogenic and vascular permeability factor. VEGF plays a key role in both pathological and physiological angiogenesis. There are many recent findings regarding the role of VEGF in diabetic microvascular and macrovascular diseases. Many approaches with VEGF-related therapies begin to treat and prevent these complications and have been used for the treatment of microvascular complications such as diabetic retinopathy, whereas VEGF agonists have been used to treat macrovascular complications such as myocardial infarction and peripheral limb ischemia. Nitric oxide (NO) is known to mediate many physiological and pathological functions, including modulation of vascular tone, permeability, and capillary growth. Recent reports indicate that NO may play an intimate role in VEGF signaling. Therefore, we hypothesized that the expression of eNOS may be regulated by VEGF. The objectives of the present study were to determine whether VEGF up-regulates the expression of endothelial NO synthase (eNOS) in endothelial cells and to elucidate the mechanism that mediate this response.
METHODS
Endothelial cells were isolated from bovine aortae. The expression of eNOS was assessed by Northern blotting analysis. To evaluate the mechanism of VEGF-induced eNOS expression, endothelial cells were conditioned with VEGF and pretreated with phorbol-12-myristate acetate (PMA), a protein kinase C (PKC) activator, or GF109203X (GFX), a PKC inhibitor. The changes of eNOS gene expression.
RESULTS
VEGF significantly increased the expression of eNOS mRNA in bovine aortic endothelial cells (BAEC) in time and dose dependent manners. PMA increased the expression of eNOS mRNA, as well as the VEGF-induced expression of eNOS mRNA in endothelial cells, while inhibition of the PKC activity, with the GFX blocked the upregulation of the VEGF-induced eNOS mRNA.
CONCLUSION
The results suggest that VEGF upregulates eNOS gene expression in aortic endothelial cells, by a PKC dependent pathway and, eNOS may be important in the development of VEGF-induced angiopathy.

Keyword

Vascular endothelial growth factor; Nitric oxide synthase; Nitric oxide; Diabetic angiopathy; Aortic endothelial cell; Protein kinase C

MeSH Terms

Angiogenesis Inducing Agents
Aorta
Blotting, Northern
Capillaries
Diabetic Angiopathies
Diabetic Retinopathy
Endothelial Cells*
Extremities
Gene Expression
Ischemia
Myocardial Infarction
Neovascularization, Physiologic
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type III*
Permeability
Protein Kinase C
RNA, Messenger
Up-Regulation
Vascular Endothelial Growth Factor A*
Angiogenesis Inducing Agents
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type III
Protein Kinase C
RNA, Messenger
Vascular Endothelial Growth Factor A