![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Pharmacology and Toxicology, Botterell Hall, Queen's University, Kingston, Ontario, Canada
Angiogenesis is necessary during embryonic development and wound healing but can be detrimental in pathologies, including cancer. Because initiation of angiogenesis involves migration and proliferation of vascular endothelial cells (VECs) and cAMP-elevating agents inhibit these events, such agents may represent a novel therapeutic avenue to controlling angiogenesis. Intracellular cAMP levels are regulated by their synthesis by adenylyl cyclases and hydrolysis by cyclic nucleotide phosphodiesterases (PDEs). In this report, we show that human VECs express variants of PDE2, PDE3, PDE4, and PDE5 families and demonstrate that the levels of these enzymes differ in VECs derived from aorta, umbilical vein, and microvascular structures. Selective inhibition of PDE2 did not increase cAMP in any VECs, whether in the absence or presence of forskolin, but it did inhibit migration of all VECs studied. Inhibition of PDE4 activity decreased migration, and in conjunction with forskolin, increased cAMP in all VECs studied. PDE3 inhibition potentiated forskolin-induced increases in cAMP and inhibited migration in VECs derived from aorta and umbilical vein but not in microvascular VECs. In experiments with combinations of PDE2, PDE3, and PDE4 inhibitors, a complex interaction between the abilities of these agents to limit human VEC migration was observed. Overall, our data are consistent with the hypothesis that PDE subtype inhibition allows different effects in distinct VEC populations and indicate that these agents may represent novel therapeutic agents to limit angiogenesis in complex human diseases.
Address correspondence to: Dr. Donald H. Maurice, Department of Pharmacology and Toxicology, Botterell Hall, Queen's University, Kingston, ON K7L 3N6, Canada. E-mail: mauriced{at}post.queensu.ca
This article has been cited by other articles:
|
|
 |
|
  J. Surapisitchat, K.-I. Jeon, C. Yan, and J. A. Beavo Differential Regulation of Endothelial Cell Permeability by cGMP via Phosphodiesterases 2 and 3 Circ. Res., October 12, 2007; 101(8): 811 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Netherton, J. A. Sutton, L. S. Wilson, R. L. Carter, and D. H. Maurice Both Protein Kinase A and Exchange Protein Activated by cAMP Coordinate Adhesion of Human Vascular Endothelial Cells Circ. Res., October 12, 2007; 101(8): 768 - 776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Senthilkumar, R. D. Smith, J. Khitha, N. Arora, S. Veerareddy, W. Langston, J. H. Chidlow Jr, S. C. Barlow, X. Teng, R. P. Patel, et al. Sildenafil Promotes Ischemia-Induced Angiogenesis Through a PKG-Dependent Pathway Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): 1947 - 1954. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Busch, H. Liu, A. R. Graveline, and K. D. Bloch Nitric oxide induces phosphodiesterase 4B expression in rat pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L747 - L753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Houslay The Long and Short of Vascular Smooth Muscle Phosphodiesterase-4 As a Putative Therapeutic Target Mol. Pharmacol., September 1, 2005; 68(3): 563 - 567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Zhu, S. Strada, and T. Stevens Cyclic GMP-specific phosphodiesterase 5 regulates growth and apoptosis in pulmonary endothelial cells Am J Physiol Lung Cell Mol Physiol, August 1, 2005; 289(2): L196 - L206. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
