In Vivo Evidence for a Myogenic Response in the Fetal Pulmonary Circulation

Abstract

In vitro studies have suggested that pulmonary arteries can exhibit a myogenic response and that this myogenic response may be potent during the perinatal period. However, whether a myogenic response can be demonstrated to exist in vivo and the potential role of the myogenic response on the regulation of pulmonary blood flow during fetal life is unknown. We hypothesized that an acute increase in pulmonary artery pressure resulting from partial compression of the ductus arteriosus (DA) in the fetus may simultaneously activate two opposing responses: 1) blood flow-induced vasodilation (owing to shear stress); and 2) pressure-induced vasoconstriction (owing to the myogenic response). To test this hypothesis, we studied the hemodynamic response to partial DA compression with and without inhibition of shear stress-induced vasodilation by nitric oxide synthase blockade in chronically prepared late-gestation fetal lambs. Without inhibition of nitric oxide synthase, pulmonary vascular resistance progressively decreased by 39 +/- 5% during the DA compression period (p < 0.05). In contrast, DA compression after nitric oxide synthase inhibition caused left pulmonary artery blood flow to initially increase and then steadily decrease toward a plateau value, and caused pulmonary vascular resistance to progressively increase by 28 +/- 4% above baseline (p < 0.05). The plateau value of pulmonary vascular resistance was reached in less than 5 min after the onset of DA compression. Left pulmonary artery blood flow after 10 min of partial DA compression did not change with the rise in pulmonary artery pressure; plateau values of pulmonary vascular resistance increased linearly with the increase in pulmonary artery pressure. These results support the hypothesis that the perinatal lung circulation has a potent myogenic response, and that this response may be masked in vivo under physiologic conditions by nitric oxide synthase activity. We speculate that the myogenic response may become a predominant regulatory mechanism of pulmonary vascular resistance when endothelium-dependent vasoreactivity is impaired, such as in persistent pulmonary hypertension of the newborn.

Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells

“…Ductal ligation initially induces a large increase in pulmonary blood flow followed by a return to baseline flow while PA pressure remains high (1). In vivo experiments suggest that the fetal pulmonary circulation exhibits a myogenic response, where pressure-induced vasoconstriction opposes the initial increase in pulmonary blood flow following ductal ligation (43). Although the underlying mechanisms are incompletely understood, they involve impaired nitric oxide (NO) synthase (NOS)-mediated vasodilation and increased levels of reactive oxygen species (ROS) (23,43).…”

“…In vivo experiments suggest that the fetal pulmonary circulation exhibits a myogenic response, where pressure-induced vasoconstriction opposes the initial increase in pulmonary blood flow following ductal ligation (43). Although the underlying mechanisms are incompletely understood, they involve impaired nitric oxide (NO) synthase (NOS)-mediated vasodilation and increased levels of reactive oxygen species (ROS) (23,43). PPHN lambs also exhibit elevated pulmonary vascular oxidant stress relative to control lambs (7,50), and recent studies have demonstrated improved oxygenation in ventilated PPHN lambs that received intratracheal antioxidants at birth (13,49,50).…”

Noninvasive Assessment of Fetal Pulmonary Blood Flow in Experimental Pulmonary Hypertension in the Fetal Lamb

“…However, the temporary pulmonary high blood flow derived from our Doppler study seemed to be more sustained compared with the one reported by Abman, in which the LPA blood flow returned to baseline value 2-3 h after the DA compression, whereas LPA pressure and resistance remained high. In an additional study by this group, the normalization of pulmonary blood flow was found to be related to myogenic response (22). We found that the surgical creation of the fistula was associated with a rapid increase of the pulmonary blood flow (in the first 30 min; n ϭ 2 fetuses) and that this high blood flow was sustained for at least 24 h. This delay in the normalization of pulmonary blood flow may reflect a less pronounced or delayed myogenic response in the fistula model.…”

Pulmonary Hypertension Caused by Pulmonary Venous Hypertension

“…Passive distention of small pulmonary vessels at least partly accounts for the flow-mediated decrease in PVR, 91 which seems inconsistent with the notion of distention-mediated vasoconstriction. Storme and colleagues, 86 however, showed that, in the fetal lung, vasoconstriction with ductal compression occurs only when endothelial release of NO is blocked using NO synthase inhibition. They surmise that increased PA flow with ductal constriction causes endothelial release of NO, which prevents smooth muscle activation, but when NO production is inhibited, myogenic contraction is made manifest.…”

“…80 There is ample reason to think that myogenic constriction can also occur in the lung: first, stretch or increased intraluminal pressure stimulates constriction in segments of small PAs in vitro in multiple species, [81][82][83][84][85] and second, myogenic tone, at physiologically relevant pressures, has been demonstrated in the in situ lung of the ovine fetus 86,87 and (pace assertions that this response is lacking in normoxic mature animals 88 ) mature feline, canine, and ovine lungs. 42,89,90 An apparent objection to the pulmonary myogenic tone hypothesis is the observed effect of exercise on PVR (it generally decreases it).…”