Response Gene to Complement 32 Maintains Blood Pressure Homeostasis by Regulating α-Adrenergic Receptor Expression.

Rationale: Hypertension prevalence is much higher among children and adolescents with low birth weight and greater postnatal weight gain than in individuals with normal birth weight. However, the cause and molecular mechanisms underlying this complication remain largely unknown. Our previous studies have shown that RGC-32 (response gene to complement 32)-deficient (RGC-32) mice are born significantly smaller but grow faster than their WT (wild type) controls, which allows adult RGC-32 mice to attain body weights similar to those of control mice.

Juvenile growth reduces the influence of epithelial sodium channels on myogenic tone in skeletal muscle arterioles.

Previous studies have documented that rapid juvenile growth is accompanied by functional changes in the arteriolar endothelium, but much less is known about functional changes in arteriolar smooth muscle over this period. In this study, we investigate the possible contribution of epithelial sodium channels (ENaC) to the myogenic behaviour of arterioles at two stages of juvenile growth. The effects of the ENaC inhibitor benzamil on different levels of myogenic tone were studied in isolated gracilis muscle arterioles from rats aged 21-28 days ("weanlings") and 42-49 days ("juveniles").

Salt, Angiotensin II, Superoxide, and Endothelial Function.

Proper function of the vascular endothelium is essential for cardiovascular health, in large part due to its antiproliferative, antihypertrophic, and anti-inflammatory properties. Crucial to the protective role of the endothelium is the production and liberation of nitric oxide (NO), which not only acts as a potent vasodilator, but also reduces levels of reactive oxygen species, including superoxide anion (O2•-). Superoxide anion is highly injurious to the vasculature because it not only scavenges NO molecules, but has other damaging effects, including direct oxidative disruption of normal signaling mechanisms in the endothelium and vascular smooth muscle cells.

The effect of high salt intake on endothelial function: reduced vascular nitric oxide in the absence of hypertension.

Within the last 25 years, it has become increasingly clear that high dietary salt intake represents a risk factor for the development of cardiovascular disease that is independent of its well-known ability to increase arterial pressure in some individuals. Studies in normotensive experimental animals and human subjects have revealed that a key feature of this pressure-independent effect of dietary salt is a profound reduction in vascular nitric oxide (NO) bioavailability that limits endothelium-dependent dilation. This reduction in NO is strongly associated with increased levels of reactive oxygen species (ROS) generated by NAD(P)H oxidase, xanthine oxidase or uncoupled endothelial NO synthase within the vascular wall, leading not only to scavenging of NO but also to disruption of some signaling pathways that mediate its production.

Pulmonary particulate matter and systemic microvascular dysfunction.

Pulmonary particulate matter (PM) exposure has been epidemiologically associated with an increased risk of cardiovascular morbidity and mortality, but the mechanistic foundations for this association are unclear. Exposure to certain types of PM causes changes in the vascular reactivity of several macrovascular segments. However, no studies have focused upon the systemic microcirculation, which is the primary site for the development of peripheral resistance and, typically, the site of origin for numerous pathologies.

Changes in eNOS phosphorylation contribute to increased arteriolar NO release during juvenile growth.

Nitric oxide (NO) mediates a major portion of arteriolar endothelium-dependent dilation in adults, but indirect evidence has suggested that NO contributes minimally to these responses in the young. Isolated segments of arterioles were studied in vitro to verify this age-related increase in NO release and investigate the mechanism by which it occurs. Directly measured NO release induced by ACh or the Ca(2+) ionophore A-23187 was five- to sixfold higher in gracilis muscle arterioles from 42- to 46-day-old (juvenile) rats than in those from 25- to 28-day-old (weanling) rats.

Salt modulates vascular response through adenosine A(2A) receptor in eNOS-null mice: role of CYP450 epoxygenase and soluble epoxide hydrolase.

High salt (HS) intake can change the arterial tone in mice, and the nitric oxide (NO) acts as a mediator to some of the receptors mediated vascular response. The main aim of this study was to explore the mechanism behind adenosine-induced vascular response in HS-fed eNOS(+/+) and eNOS(-/-) mice The modulation of vascular response by HS was examined using aortas from mice (eNOS(+/+) and eNOS(-/-)) fed 4% (HS) or 0.45% (NS) NaCl-diet through acetylcholine (ACh), NECA (adenosine-analog), CGS 21680 (A(2A) AR-agonist), MS-PPOH (CYP epoxygenase-blocker; 10(-5) M), AUDA (sEH-blocker; 10(-5) M), and DDMS (CYP4A-blocker; 10(-5) M).

Endothelium-dependent control of vascular tone during early postnatal and juvenile growth.

Endothelial dysfunction can develop at an early age in children with risk factors for cardiovascular disease. A clear understanding of the nature of this dysfunction and how it can worsen over time requires detailed information on the normal growth-related changes in endothelial function on which the pathological changes are superimposed. This review summarizes our current understanding of these normal changes, as derived from studies in four different mammalian species.

Modulation by salt intake of the vascular response mediated through adenosine A(2A) receptor: role of CYP epoxygenase and soluble epoxide hydrolase.

High-salt intake can change the effect of adenosine on arterial tone in mice. The aim of this study was to clarify the mechanism by which this occurs. Using aortas from mice fed a 4% NaCl (HS) or 0.

Decreased arteriolar tetrahydrobiopterin is linked to superoxide generation from nitric oxide synthase in mice fed high salt.

Objective: Impaired endothelium-dependent arteriolar dilation in mice fed high salt (HS) is due to local oxidation of nitric oxide (NO) by superoxide anion (O(2) (-)). We explored the possibility that "uncoupled" endothelial nitric oxide synthase (eNOS) is the source of this O(2) (-).

Methods: Levels of L-arginine (L-Arg), tetrahydrobiopterin (BH(4)), and O(2) (-) (hydroethidine oxidation) were measured in spinotrapezius muscle arterioles of mice fed normal salt (0.

Growth-dependent changes in the contribution of carbon monoxide to arteriolar function.

Background/aims: Endothelium-dependent dilation of skeletal muscle arterioles is mediated by unknown factors in very young rats. We assessed the possible contribution of carbon monoxide (CO) to this dilation and to dilation in older animals.

Methods: The effects of de-endothelialization or various pharmacological inhibitors on responses to CO or endothelium-dependent dilators were studied in gracilis muscle arterioles from rats at 3-4 weeks ('weanlings') and 6-7 weeks ('juveniles').

Integration of skeletal muscle resistance arteriolar reactivity for perfusion responses in the metabolic syndrome.

Previous study suggests that with evolution of the metabolic syndrome, patterns of arteriolar reactivity are profoundly altered and may constrain functional hyperemia. This study investigated interactions between parameters of vascular reactivity at two levels of resistance arterioles in obese Zucker rats (OZR), translating these observations into perfusion regulation for in situ skeletal muscle. Dilation of isolated and in situ resistance arterioles from OZR to acetylcholine, arachidonic acid (AA), and hypoxia (isolated arterioles only) were blunted vs.

Pulmonary nanoparticle exposure disrupts systemic microvascular nitric oxide signaling.

We have shown that pulmonary nanoparticle exposure impairs endothelium dependent dilation in systemic arterioles. However, the mechanism(s) through which this effect occurs is/are unclear. The purpose of this study was to identify alterations in the production of reactive species and endogenous nitric oxide (NO) after nanoparticle exposure, and determine the relative contribution of hemoproteins and oxidative enzymes in this process.

High-salt diet enhances mouse aortic relaxation through adenosine A2A receptor via CYP epoxygenases.

We hypothesize that A(2A) adenosine receptors (A(2A) AR) promote aortic relaxation in mice through cytochrome P450 (CYP)-epoxygenases and help to avoid salt sensitivity. Aortas from male mice maintained on a high-salt (HS; 7% NaCl) or normal-salt (NS; 0.45% NaCl) diet for 4-5 wks were used.

Increased myogenic responsiveness of skeletal muscle arterioles with juvenile growth.

Previous studies from this laboratory suggest that during juvenile growth, structural changes in the arteriolar network are accompanied by changes in some of the mechanisms responsible for regulation of tissue blood flow. To test the hypothesis that arteriolar myogenic behavior is altered with growth, we studied gracilis muscle arterioles isolated from Sprague-Dawley rats at two ages: 21-28 and 42-49 days. When studied at their respective in vivo pressures, the myogenic index (instantaneous slope of the active pressure-diameter curve) of arterioles from 42-49-day-old rats was more negative than that of arterioles from 21-28-day-old rats, indicating greater myogenic responsiveness.

Hydrogen peroxide emerges as a regulator of tone in skeletal muscle arterioles during juvenile growth.

Objective: The endothelium-dependent dilation of skeletal muscle arterioles is mediated by factors that have not been identified in young rats, and partly mediated by an unidentified hyperpolarizing factor in maturing rats. This study was designed to determine if endogenous hydrogen peroxide (H2O2) contributes to this arteriolar dilation at either of these growth stages.

Methods: Gracilis muscle arterioles were isolated from rats at ages 24-26 days ("weanlings") and 46-48 days ("juveniles").

Hydrogen peroxide-dependent arteriolar dilation in contracting muscle of rats fed normal and high salt diets.

Objective: High dietary salt intake decreases the arteriolar dilation associated with skeletal muscle contraction. Because hydrogen peroxide (H2O2) can be released from contracting muscle fibers, this study was designed to assess the possible contribution of H2O2 to skeletal muscle functional hyperemia and its sensitivity to dietary salt.

Methods: The authors investigated the effect of catalase treatment on arteriolar dilation and hyperemia in contracting spinotrapezius muscle of rats fed a normal salt (0.

High salt intake reduces endothelium-dependent dilation of mouse arterioles via superoxide anion generated from nitric oxide synthase.

In skeletal muscle arterioles of normotensive rats fed a high salt diet, the bioavailability of endothelium-derived nitric oxide (NO) is reduced by superoxide anion. Because the impact of dietary salt on resistance vessels in other species is largely unknown, we investigated endothelium-dependent dilation and oxidant activity in spinotrapezius muscle arterioles of C57BL/6J mice fed normal (0.45%, NS) or high salt (7%, HS) diets for 4 wk.

High dietary salt reduces the contribution of 20-HETE to arteriolar oxygen responsiveness in skeletal muscle.

The coupling of tissue blood flow to cellular metabolic demand involves oxygen-dependent adjustments in arteriolar tone, and arteriolar responses to oxygen can be mediated, in part, by changes in local production of 20-HETE. In this study, we examined the long-term effect of dietary salt on arteriolar oxygen responsiveness in the exteriorized, superfused rat spinotrapezius muscle and the role of 20-HETE in this responsiveness. Rats were fed either a normal-salt (NS, 0.

Growth-dependent changes in endothelial factors regulating arteriolar tone.

Previous studies from this laboratory suggest that during maturation, rapid microvascular growth is accompanied by changes in the mechanisms responsible for regulation of tissue blood flow. To further define these changes, we studied isolated gracilis muscle arterioles from weanling ( approximately 25 days) and juvenile ( approximately 44 days) Sprague-Dawley rats to test the hypothesis that endothelial mechanisms for the control of arteriolar tone are altered with growth. Responses to the endothelium-dependent dilator acetylcholine (ACh) were greater in weanling arterioles (WA) than in juvenile arterioles (JA), whereas there were no consistent differences between age groups in arteriolar responses to other endothelium-dependent agonists (A-23187, vascular endothelial growth factor, and simvastatin).

Systemic microvascular dysfunction and inflammation after pulmonary particulate matter exposure.

The epidemiologic association between pulmonary exposure to ambient particulate matter (PM) and cardiovascular dysfunction is well known, but the systemic mechanisms that drive this effect remain unclear. We have previously shown that acute pulmonary exposure to PM impairs or abolishes endothelium-dependent arteriolar dilation in the rat spinotrapezius muscle. The purpose of this study was to further characterize the effect of pulmonary PM exposure on systemic microvascular function and to identify local inflammatory events that may contribute to these effects.

Functional hyperemia is reduced in skeletal muscle of aged rats.

Objective: To test the hypothesis that active hyperemia is reduced in skeletal muscle of old rats due to a decreased bioavailability of prostanoids, which in turn is due to increased oxidative stress.

Methods: The microvasculature of the spinotrapezius muscle of 3-, 12-, and 24-month male Sprague-Dawley rats was examined using in vivo videomicroscopy. Arteriolar diameter and centerline red cell velocity were measured in resting and contracting muscle.

Reduced arteriolar responses to skeletal muscle contraction after ingestion of a high salt diet.

We previously reported that in skeletal muscle arterioles of rats fed a very high salt (HS; 7%) diet, the bioavailability of endothelium-derived nitric oxide (NO) is reduced through scavenging by reactive oxygen species. Because arteriolar NO can play an important role in local blood flow control, we investigated whether arteriolar responses to increased tissue metabolism become compromised in skeletal muscle of salt-fed rats. Consumption of a HS (4%) diet for 4 weeks had no effect on arteriolar diameters, volume flow or shear stress in resting spinotrapezius muscle.

Calcium-independent release of endothelial nitric oxide in the arteriolar network: onset during rapid juvenile growth.

Objective: In young rats, skeletal muscle arterioles respond to acetylcholine, which elicits Ca2+-dependent endothelial nitric oxide (NO) release, but not to shear stress, which does not require increased intracellular Ca2+ for endothelial NO release. The aim of this study was to determine if, in general, signaling pathways for endothelial NO release that differ in their reliance on Ca2+ may be developing at different times during normal arteriolar network growth in skeletal muscle.

Methods: Arteriolar responses to intraluminal infusion of the Ca2+ ionophore A23187, and the Ca2+-independent agonists vascular endothelial growth factor (VEGF) and simvastatin, were studied before and during NO synthase (NOS) inhibition with NG-monomethyl-L-arginine (L-NMMA) in the exteriorized spinotrapezius muscle of weanling (age 4-5 wks) and juvenile (7-8 wks) rats.

Particulate matter exposure impairs systemic microvascular endothelium-dependent dilation.

Acute exposure to airborne pollutants, such as solid particulate matter (PM), increases the risk of cardiovascular dysfunction, but the mechanisms by which PM evokes systemic effects remain to be identified. The purpose of this study was to determine if pulmonary exposure to a PM surrogate, such as residual oil fly ash (ROFA), affects endothelium-dependent dilation in the systemic microcirculation. Rats were intratracheally instilled with ROFA at 0.