Maturation Alters Cyclic Nucleotide and Relaxation Responses to Nitric Oxide Donors in Ovine Cerebral Arteries

Nauli, Surya M.; White, Charles R.; Hull, Andrew; Pearce, William J.

doi:10.1159/000067959

Cited by 11 publications

(9 citation statements)

References 28 publications

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“…In a subsequent study in which a similar degree of hypoxia was maintained isocapnic, fetal cortical CBF increased ~50% above baseline [71, 257]. In agreement with findings of a major role for NO in developing, as compared to adult, MCA, the efficacy of NO donors [255] as were basal levels of both cAMP and cGMP, were generally greater in newborn than adult MCA (Table 4 ). …”

Section: Vasorelaxation Pathways/responsessupporting

confidence: 71%

“…In a subsequent publication, these authors confirmed the 8-pCPT-cGMP decreases in K + - and 5-HT-induced maximum contractility and CaS [275] (Table 4 ). The ratio of basal levels of cGMP to cAMP also were considerably greater in newborn than adult MCA [255] (Table 4 ). In addition, in newborn CCA, the Km value for phosphodiesterase, which metabolizes cGMP to GMP, was twice that of adult [254].…”

Section: Vasorelaxation Pathways/responsesmentioning

confidence: 99%

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Cerebral Artery Signal Transduction Mechanisms: Developmental Changes in Dynamics and Ca<sup>2+</sup> Sensitivity

Longo¹,

Goyal²

2013

CVP

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As compared to the adult, the developing fetus and newborn infant are at much greater risk for dysregulation of cerebral blood flow (CBF), with complications such as intraventricular and germinal matrix hemorrhage with resultant neurologic sequelae. To minimize this dysregulation and its consequences presents a major challenge. Although in many respects the fundamental signal transduction mechanisms that regulate relaxation and contraction pathways, and thus cerebrovascular tone and CBF in the immature organism are similar to those of the adult, the individual elements, pathways, and roles differ greatly. Here, we review aspects of these maturational changes of relaxation/contraction mechanisms in terms of both electro-mechanical and pharmaco-mechanical coupling, their biochemical pathways and signaling networks. In contrast to the adult cerebrovasculature, in addition to attenuated structure with differences in multiple cytoskeletal elements, developing cerebrovasculature of fetus and newborn differs in many respects, such as a strikingly increased sensitivity to [Ca2+]i and requirement for extracellular Ca2+ for contraction. In essence, the immature cerebrovasculature demonstrates both “hyper-relaxation” and “hypo-contraction”. A challenge is to unravel the manner in which these mechanisms are integrated, particularly in terms of both Ca2+-dependent and Ca2+-independent pathways to increase Ca2+ sensitivity. Gaining an appreciation of these significant age-related differences in signal mechanisms also will be critical to understanding more completely the vulnerability of the developing cerebral vasculature to hypoxia and other stresses. Of vital importance, a more complete understanding of these mechanisms promises hope for improved strategies for therapeutic intervention and clinical management of intensive care of the premature newborn.

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Section: Vasorelaxation Pathways/responsessupporting

confidence: 71%

Section: Vasorelaxation Pathways/responsesmentioning

confidence: 99%

Cerebral Artery Signal Transduction Mechanisms: Developmental Changes in Dynamics and Ca<sup>2+</sup> Sensitivity

Longo¹,

Goyal²

2013

CVP

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“…To examine effects of cAMP on cilia function, we determined the biological function by studying a typical logarithmic scale dose-response curve (log e (x)) [8,9]. Likewise, we used the same mathematical function for the cAMP measurement, which was also suggested by the manufacturer.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms regulating cilia growth and cilia function in endothelial cells

Abdul-Majeed

Moloney

Nauli

2011

Cell. Mol. Life Sci.

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The primary cilium is an important sensory organelle present in most mammalian cells. Our current studies aim at examining intracellular molecules that regulate cilia length and/or cilia function in vitro and ex vivo. For the first time, we show that intracellular cAMP and cAMP-dependent protein kinase (PKA) regulate both cilia length and function in vascular endothelial cells. Although calcium-dependent protein kinase modulates cilia length, it does not play a significant role in cilia function. Cilia length regulation also involves mitogen-activated protein kinase (MAPK), protein phosphatase-1 (PP-1), and cofilin. Furthermore, cofilin regulates cilia length through actin rearrangement. Overall, our study suggests that the molecular interactions between cilia function and length can be independent of one another. Although PKA regulates both cilia length and function, changes in cilia length by MAPK, PP-1, or cofilin do not have a direct correlation to changes in cilia function. We propose that cilia length and function are regulated by distinct, yet complex intertwined signaling pathways.

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“…In contrast to some other preparations (37), nitric oxide (NO) is the primary vasodilator molecule released from the endothelium of both mature and immature ovine carotid arteries (33); therefore, the combined evidence suggests that in these arteries, postnatal maturation must increase either vascular sensitivity to NO and/or endothelial NO release (34). As we have demonstrated previously (22), vasorelaxant sensitivity to NO is not increased by postnatal maturation, which suggests that maturation enhances NO release in response to endothelial activation. The present studies were designed to explore this hypothesis.…”

mentioning

confidence: 93%

Maturation enhances fluid shear-induced activation of eNOS in perfused ovine carotid arteries

White

Hamade²,

Siami³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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The present study tests the hypothesis that age-dependent increases in endothelial vasodilator capacity are due to maturational increases in endothelial nitric oxide (NO) synthesis and release. Intact 4-cm carotid artery segments taken from term fetal lambs and nonpregnant adult sheep were perfused by using a closed system that enabled independent control of flow and inflow pressure and facilitated complete recovery of all NO released. Fluid shear stress induced a graded release of NO (in nmol NO x min x cm(-2) of luminal surface area) that was significantly greater in adult (890 +/- 140) than in fetal (300 +/- 40) carotid arteries at corresponding values of shear stress (5.9 +/- 0.3 dyn/cm2) but was independent of inflow pressure in both age groups. These age-related differences in NO release were not attributable to corresponding differences in endothelial NO synthase (eNOS) abundance, as eNOS protein levels (in ng of eNOS/cm2 of luminal surface area) were similar in adult (14 +/- 2) and fetal (12 +/- 1) arteries. Adult (80 +/- 15) and fetal (89 +/- 32) levels of eNOS mRNA (in 10(6) copies/cm2 of luminal surface area) were also similar. However, when NO release was normalized relative to the associated mass of eNOS protein to estimate eNOS-specific activity in situ, this value (in nmol NO x microg of eNOS(-1) x min(-1)) was significantly greater in adult (177 +/- 44) than in fetal (97 +/- 36) arteries when the endothelium was maximally activated by A-23187. Similarly, the slope of the relation between fluid shear stress and estimated eNOS-specific activity (in nmol NO x microg of eNOS(-1) x min(-1) per dyn/cm2) was also significantly greater in adult (6.8 +/- 0.1) than in fetal (2.9 +/- 0.1) arteries, which suggests that eNOS may be more sensitive to or more efficiently coupled to activating stimuli in adult compared with fetal arteries. We conclude that maturational increases in endothelial vasodilator capacity are attributable to age-dependent increases in NO release secondary to elevated eNOS-specific activity and involve more efficient coupling between endothelial activation and enhancement of eNOS activity in adult compared with fetal arteries.

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Maturation Alters Cyclic Nucleotide and Relaxation Responses to Nitric Oxide Donors in Ovine Cerebral Arteries

Cited by 11 publications

References 28 publications

Cerebral Artery Signal Transduction Mechanisms: Developmental Changes in Dynamics and Ca<sup>2+</sup> Sensitivity

Cerebral Artery Signal Transduction Mechanisms: Developmental Changes in Dynamics and Ca<sup>2+</sup> Sensitivity

Mechanisms regulating cilia growth and cilia function in endothelial cells

Maturation enhances fluid shear-induced activation of eNOS in perfused ovine carotid arteries

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