Biology Reference
In-Depth Information
vasoconstrictors include hypoxia (a defining feature of fetal development), as well
as endothelin-1 (ET-1), thromboxane, acidosis, and various mediators of inflam-
mation (Lakshminrusimha and Steinhorn
1999
).
As gestation progresses, the mediators of pulmonary vasodilation become more
dominant. In particular, pulmonary expression of endothelial nitric oxide (NO)
synthase (eNOS), inducible NO synthase (iNOS), and NO production increase near
the time of birth (Abman et al.
1990
; Shaul et al.
2002
). Coincident increases in
soluble guanylate cyclase (sGC) activity promote increased vascular cGMP, which
then leads to vasorelaxation via decreasing intracellular calcium (Bloch et al.
1997
).
Another potentially important vasodilatory pathway in the fetal lung is the prosta-
cyclin pathway. Cyclooxygenase (COX) is the rate-limiting enzyme that generates
prostacyclin from arachadonic acid. COX-1 in particular is upregulated in late
gestation (Brannon et al.
1994
,
1998
), leading to an increase in prostacyclin
production in late gestation and early postnatal life (Brannon et al.
1994
; Leffler
et al.
1984
). Prostacyclin upregulates adenylyl cyclase to increase intracellular
cAMP levels, which then lead to vasorelaxation.
Phosphodiesterases (PDEs) counteract these cAMP and cGMP vasodilatory
pathways, and as described extensively within this text, they comprise a super-
family of enzymes that includes 11 different PDE families with specific tissue and
cellular distributions (Conti and Beavo
2007
; Lugnier
2006
). The prevalent PDE
within the lung is PDE5, although there are significant amounts of PDE1, PDE3,
and PDE4 as well (Maclean et al.
1997
). PDE5, a cGMP-specific PDE, was initially
characterized in bovine lung and has since been found in multiple other tissues
(Loughney et al.
1998
). In rats, PDE5 expression and activity steadily increase
through the end of gestation, peak on day of life one, and then drop dramatically
into adulthood, strongly suggesting developmental regulation (Sanchez et al.
1998
).
In contrast, in neonatal lambs, PDE5 activity and expression appear to acutely
decrease within 1 h after birth and then rise again at 4-7 days of life (Farrow et al.
2008a
; Hanson et al.
1998a
; Okogbule-Wonodi et al.
1998
; Sanchez et al.
1998
).
Furthermore, PDE5 activity is higher in pulmonary arteries than pulmonary veins in
lambs, suggesting location-dependent as well as developmental regulation (Okog-
bule-Wonodi et al.
1998
). As the primary enzyme responsible for regulating cGMP,
PDE5 potentially represents the most important regulator of NO-mediated vascular
relaxation in the normal pulmonary vascular transition after birth (Abman et al.
1990
; Lakshminrusimha and Steinhorn
1999
).
Unlike PDE5, less is known about the developmental regulation of other cGMP
PDEs in the fetal and neonatal lung. PDE1, a dual specificity PDE, consists of
three isoforms in mammals; PDE1A and PDE1B have higher affinity for cGMP
but hydrolyze both cyclic nucleotides with similar efficacy. In contrast, PDE1C
hydrolyzes cGMP and cAMP with equal affinity and rate. All three isoforms of
PDE1 have been described in the pulmonary vasculature of various animals and in
human pulmonary artery smooth muscle cells (Evgenov et al.
2006
). While their
presence has been documented in older animals and adult humans, there has been
little study of PDE1 expression or activity in the perinatal period. A recent study in
neonatal mice indicates that PDE1A mRNA decreased postnatally in normoxia, but
