Vascular Endothelial Cell Cyclic Nucleotide Phosphodiesterases and Regulated Cell Migration: Implications in Angiogenesis

Abstract

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 cAMPelevating 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.

Genomewide RNA expression profiling in lung identifies distinct signatures in idiopathic pulmonary arterial hypertension and secondary pulmonary hypertension

“…Increased expression of PDE1A, PDE1C, PDE3B, and PDE5A in PAH pulmonary artery smooth muscle cells have been observed in association with decreased cAMP levels and increased proliferation of pulmonary artery smooth muscle cells in PAH patients (36). Inhibition of PDE isoforms results in relaxation of smooth muscle cells (37,43). Our data confirmed increased expression of PDE3B and also show increased expression of PDE4A, PDE4C, and PDE4D.…”

Alterations in Nitric Oxide and Endothelin-1 Bioactivity Underlie Cerebrovascular Dysfunction in ApoE-Deficient Mice

“…Moreover, in these cells, another selective PDE3 inhibitor, cilostamide, in addition to cilostazol, elevates cAMP levels (Netherton and Maurice, 2005), supporting the view that the effects of cilostazol likely relate to block of PDE3 activity. In terms of selectivity in studies using recombinant enzymes, cilostazol is approximately 200 to 400 times more potent at PDE3 (IC 50 B0.2 m mol/L) than at PDE4 and 20 times more potent at PDE5 (Sudo et al, 2000).…”

Pulmonary vascular changes in asthma and COPD

“…Intracellular cAMP levels are regulated by synthesis by adenylyl cyclases and hydrolysis by cyclic nucleotide phosphodiesterases (PDEs). Vascular endothelial cells express variable levels of PDE-2, PDE-3, PDE-4, and PDE-5 in cells derived from 26 different sources aorta, umbilical vein, and microvascular structures [143]. Selective PDE inhibitors are used in the treatment of pulmonary hypertension [144], which make them interesting for treatment of also other pulmonary diseases with vascular involvements.…”