To define the role of endothelial nitric oxide (NO) in developmental changes in pulmonary vascular resistance and oxygen responsiveness, we determined the ontogeny of endothelial NO production and of oxygen modulation of that process in pulmonary arteries from fetal and newborn lambs. NO production was assessed by measuring endothelium-dependent arterial guanosine 3',5'-cyclic monophosphate synthesis. Basal NO rose two-fold from late gestation to 1 wk of age and another 1.6-fold from 1 to 4 wk. Acetylcholine-stimulated NO also increased 1.6-fold from 1 to 4 wk. The maturational rise in NO was evident at high Po2 in vitro, and it was not modified by L-arginine. This suggests that the developmental increase may alternatively involve enhanced calcium-calmodulin-mediated mechanisms, increased expression of NO synthase, or greater availability of required cofactor(s). With an acute decline in Po2 in vitro from 680 to 150 or 40 mmHg, there was 50-88% attenuation of basal and acetylcholine-stimulated NO late in the third trimester and in the newborn but not early in the third trimester. Parallel studies of mesenteric endothelium revealed postnatal increases in basal and stimulated NO but no decline in NO at lower Po2. Ontogenic changes in endothelial NO production and in oxygen modulation of that process may be involved in the maturational decrease in vascular resistance and the development of oxygen responsiveness in the pulmonary circulation.
Alterations in endothelium-derived relaxing factor (EDRF) production or mechanism of action may be involved in the responses of the developing pulmonary vasculature to changes in oxygenation. In this study the effects of acute changes in in vitro oxygen tension on EDRF production were determined in isolated segments of ovine fetal intrapulmonary arteries (4th generation) obtained at 125-135 days of gestation (term 144 +/- 4 days). EDRF production was assessed by measuring segment guanosine 3',5'-cyclic monophosphate (cGMP) accumulation in the presence of a phosphodiesterase inhibitor. Basal (nonstimulated) cGMP production and cGMP production with acetylcholine (ACh) stimulation were dependent on the presence of the endothelium, on the availability of L-arginine, and on soluble guanylate cyclase activity, confirming that they were indicative of EDRF production. cGMP production with sodium nitroprusside (SNP) was used to discriminate changes in the sensitivity of soluble guanylate cyclase with varying conditions. With decreasing oxygen tension, basal and ACh-stimulated cGMP production were attenuated, whereas cGMP production with SNP was not, indicating oxygen modulation of EDRF production. Studies of endothelium-dependent relaxation yielded comparable findings in that the response to ACh was attenuated, but that to SNP was not altered by decreased oxygenation. In addition, the decline in endothelium-dependent relaxation with decreased oxygen tension was rapidly reversed when oxygenation was increased. Parallel experiments examining cGMP production in similarly sized mesenteric arteries revealed that the effect of oxygen on pulmonary artery EDRF production may be specific to that vascular bed. These findings indicate that oxygen selectively modulates EDRF production and endothelium-dependent relaxation in ovine fetal pulmonary arteries. Direct effects of oxygen on EDRF production may at least partially underlie the responses of the developing pulmonary circulation to changes in oxygenation.
IntroductionProstacyclin is a critical mediator of structure and function in the pulmonary circulation, causing both the inhibition of vascular smooth muscle growth and vasodilatation via the stimulation ofadenylate cyclase. To examine the potential role ofalterations in prostacyclin production or mechanism of action in chronic hypoxic pulmonary hypertension, we determined the effects of prolonged (7 d Hypoxic pulmonary hypertension is one of the critical mechanisms underlying persistent pulmonary hypertension ofthe neonate and the development of pulmonary hypertension in older children and adults with a variety of cardiac and respiratory illnesses (1, 2). This phenomenon has been well studied in the adult rat, yielding both physiologic and anatomic findings similar to those noted in the human (3-5). In the rat model, pulmonary hypertension is evident almost immediately after the onset of acute severe hypoxia, and it is also present with accompanying anatomic changes after more prolonged periods of hypoxia of milder degree. These events in the pulmonary circulation of the rat are contrasted by the maintenance of normal systemic blood pressure, mimicking the clinical experience with this problem (1, 4, 6, 7). Studies in the rat and other species indicate that locally-produced prostacyclin is important in the regulation ofvasomotor tone and vascular cell differentiation and growth in the pulmonary circulation (8, 9). These actions are mediated through the plasma membrane-bound enzyme adenylate cyclase, with prostacyclin stimulation of cyclic AMP (cAMP) production resulting in vasodilatation and the inhibition ofsmooth muscle cell growth (10, 1 1). In vivo experiments and in vitro studies with perfused isolated lung preparations have demonstrated that pulmonary production ofthis potent vasodilator increases with acute hypoxia, resulting in a degree of attenuation of the vasoconstrictor response (12,13). However, despite the initial increase in prostacyclin production, further hypoxia leads to the development of pulmonary hypertension with medial hypertrophy of muscular arteries and extension of vascular smooth muscle (VSM)' into peripheral, normally nonmuscular, arteries (3, 4). These alterations are prevented in the rat when angiotensin II is administered during the hypoxia period, most likely related to its ability to release prostaglandins (PG) (8). This suggests that changes in PG synthesis or PG-mediated mechanisms may be involved in the pathogenesis of chronic hypoxic pulmonary hypertension.To examine the potential role ofalterations in prostacyclin production or mechanism ofaction in chronic hypoxic pulmonary hypertension, we determined the effects ofprolonged (7 d) in vivo hypoxia on in vitro prostacyclin production and mediation of adenylate cyclase activity in rat main pulmonary arteries. PGE2 production and mediation ofadenylate cyclase activity were also investigated to determine if the results for prostacyclin are specific to that vasodilatory prostanoid. Based on the findings with acute hypox...
We conclude that procollagen genes are transcriptionally activated early (2 to 7 days) after angioplasty vessel injury and that collagen subsequently constitutes a major biochemical and histological component of the proliferative neointima by 30 days after angioplasty. Alterations in pathways regulating procollagen metabolism may also contribute to the accumulation of extracellular matrix and growth of the neointima in the late repair phase after vessel wall injury.
To better understand the role of prostacyclin [prostaglandin (PG) I2] in oxygen mediation of vasomotor tone in the developing lung, we determined the ontogeny of the direct effects of acute changes in oxygen on in vitro PGI2 synthesis and adenosine 3',5'-cyclic monophosphate (cAMP) production in intrapulmonary arteries from fetal and newborn lambs. In the absence of varying oxygen, PGI2 synthesis increased 6.9-fold from early to late in the third trimester, and it rose an additional 3.2-fold from late gestation to 1 wk of age, and another 2.1-fold from 1 to 4 wk. PGE2 synthesis similarly rose 4.9-fold during the third trimester, but it then fell 69% from late gestation to 1 wk of age and remained unchanged postnatally. Paralleling the developmental increase in PGI2 synthesis, basal cAMP production rose 6.2-fold from the early third trimester to 4 wk of age. In contrast, PGI2-stimulated cAMP production was similar in all age groups. With an acute decline in PO2 in vitro from 680 to 40 mmHg, PGI2 and PGE2 synthesis in fetal arteries fell 33-46 and 39-55%, respectively. In contrast, they were increased by 9-145% and 44-130%, respectively, at lower PO2 in arteries from newborn lambs. Basal cAMP production was altered by decreased oxygen in a similar manner, falling by 35-39% in fetal arteries yet increasing by 21-47% in the newborn. PGI2-stimulated cAMP production, however, was not affected by oxygen at all ages except in the early third trimester. Thus there is a dramatic developmental increase in pulmonary arterial PGI2 synthesis that causes a marked maturational rise in cAMP production.(ABSTRACT TRUNCATED AT 250 WORDS)
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