Phosphodiesterases as Targets for Intermittent Claudication - Phosphodiesterases as Drug Targets - page 218

The latter elevates cAMP indirectly, and could explain the observed inhibition of
platelet activation by PDE5 inhibitors.
3.2 Vascular Smooth Muscle Cells
VSMCs have been defined to exist in two distinct phenotypes: (1) the contractile/
quiescent state, which functions primarily to regulate blood vessel size in healthy
undamaged blood vessels, and (2) the proliferative/migratory state, which is asso-
ciated mainly with the development of pathological conditions (Maurice et al.
2003 ), such as the development of plaque and restenosis (renarrowing of an artery
previously treated by angioplasty or stenting). Both cAMP and cGMP can produce
relaxation of VSMCs. While PDEs 1, 2, 3, 4, and 5 are reportedly expressed in
VSMCs (Maurice et al. 2003 ), only inhibitors of PDE3 and 5 have demonstrated
significant effects on relaxation. PDE3 inhibitors produce broad vasodilatory
effects in vitro and in vivo. Vasorelaxation by PDE5 inhibitors is more profound
in the penile corpus cavernosum and the pulmonary arteries. PDE3 inhibitors, in
particular cilostazol, reduce VSMC proliferation in vitro and significantly slow the
restenosis process in animals and patients (see Sect. 4.1.3.1 ). Thus, PDE3 inhibitors
can modulate both phenotypes of VSMCs by relaxing the contractile cells and
inhibiting the proliferative cells.
3.3 Endothelium
The expression of PDEs in vascular endothelium varies depending in different
vascular beds, with PDEs 2, 3, 4, and 5 as the most often detected (Keravis et al.
2007 ; Netherton and Maurice 2005 ). The expression levels are also influenced by
the phenotypic state (quiescent as in the healthy state, and proliferative as in the
angiogenic state) (Keravis et al. 2007 ), and in vitro culture conditions (Ashikaga
et al. 1997 ). Elevation of cAMP via inhibition of PDE4 inhibits cell proliferation,
migration, and cell cycle progression in vascular endothelial cells (Keravis et al.
2007 ; Netherton and Maurice 2005 ). Similar effects have also been observed using
PDE5 inhibitors (Zhu et al. 2005 ). In addition, increases in cAMP via inhibition of
either PDE3 (Yang et al. 2006 ; Torii et al. 2007 ) or PDE4 (Sanz et al. 2007 ;
Thompson et al. 2002 ) resulted in decreased leukocyte-endothelium interaction
and a reduction of microvascular permeability. Thus, PDE3 and PDE4 inhibitors
may offer protection for the endothelium under ischemia or inflammatory stress.
3.4 Adipocytes
PDE3B is the major PDE isoform expressed in adipocytes, and its inhibition
increases lipolysis (Snyder 1999 ; Snyder et al. 2005 ). Increased lipolysis was