Biology Reference
In-Depth Information
was increased by exposure to hyperoxia for 21 days, although PDE1A protein
expression remained unchanged (Woyda et al.
2009
). Thus, regulation of PDE1
in the neonatal pulmonary vasculature is unclear, and further investigation is
needed.
As described above, prostacyclin-cAMP signaling operates in parallel to the
NO-cGMP pathway for perinatal pulmonary vasodilation and is regulated in
part by cAMP-hydrolyzing PDEs such as PDE3 and PDE4. Our group recently
published that PDE3A expression and activity in the resistance pulmonary arteries
increase dramatically by 24 h after birth. These results were surprising and unex-
pected, as we would have predicted that similar to PDE5, PDE3 activity would
decrease after birth to facilitate increased cAMP levels (Chen et al.
2009
). This
increase may be acting to establish cAMP-containing regulatory regions within the
pulmonary vascular smooth muscle cell after birth, although it is unclear what role
PDE3 has in normal pulmonary vascular transition after birth.
Even less is known about the perinatal regulation of PDE4, which has strong
specificity for cAMP hydrolysis. PDE4 in the lung has been most extensively
studied in the airway smooth muscle (Fan Chung
2006
). However, more recent
studies have demonstrated the presence of PDE4 in adult human pulmonary
artery smooth muscle cells and that exposure to hypoxia increases expression
of several PDE4 isoforms without impacting total PDE4 activity (Millen et al.
2006
). Thus, while no one has specifically examined PDE4 around the time of
birth, it is plausible to hypothesize that PDE4 might be differentially regulated
between the relatively hypoxic in utero environment and the normoxic extra-
uterine environment.
At birth, a rapid and dramatic decrease in pulmonary vascular resistance allows
half of the combined ventricular output to be redirected from the placenta to the
lung, leading to an eight- to tenfold increase in pulmonary blood flow. The stimuli
that seem to be most important are lung inflation with a gas, a decrease in carbon
dioxide tension, and an increase in oxygen tension. Each of these stimuli will
independently decrease PVR and increase pulmonary blood flow, with the largest
effects seen when the two events occur simultaneously. For instance, oxygen
directly and indirectly stimulates the activity of both eNOS and COX-1 immedi-
ately after birth, leading to increased levels of the vasodilators, NO and prostacyclin
(Shaul et al.
1992
; Shaul and Wells
1994
; Steinhorn et al.
1994
). Shear stress is also
known to regulate the synthesis of NO in the fetal circulation. During transition, the
initial increase in pulmonary blood flow in response to ventilation or oxygenation
likely leads to increased shear stress in the vasculature, which further potentiates
NO production (Uematsu et al.
1995
). In contrast, PDE5 expression and activity
fall after birth in the pulmonary vasculature, further accentuating upstream
effects leading to increased cGMP and vasodilation (Farrow et al.
2008a
;
Sanchez et al.
1998
). It is unclear which specific signals cause PDE5 to fall as
part of the normal transition. However, if events in utero and at the time of birth
impair these critical transition steps, they may lead to elevated pulmonary pres-
sures and the symptomatic infant with persistent pulmonary hypertension of the
newborn (PPHN).
