Reactive oxygen species (ROS) have been considered for many years as negative regulators in the cardiovascular system. Indeed, excessive production of ROS characterizes many cardiovascular diseases. ...The damaging effect of ROS can be especially pronounced in a newborn organism, since during this period their vasoconstrictor effect in pulmonary arteries remains as high as in pre-term fetus and the antioxidant systems have not yet formed. Therefore, in the first hours and days of independent life, pulmonary arteries tend to contract, primarily due to the low bioavailability of endothelial NO, which increases the risk of developing pulmonary hypertension in newborns. At the same time, during the perinatal period, ROS play an important role in the adaptive reactions of the circulatory system. ROS provide occlusion of the ductus arteriosus and separation of the pulmonary and systemic circulations soon after birth, and also contribute to the contraction of peripheral vessels during hypoxia, which often accompanies the delivery, and therefore provide priority blood supply to the brain in these conditions. The vasomotor effect of ROS is also pronounced in early postnatal ontogenesis, but it has a different character. In the first weeks of life, the action of ROS serves as one of the mechanisms for increasing endothelium-dependent relaxation of pulmonary vessels. In addition, during early postnatal ontogeny, ROS may play an important role in the regulation of systemic vascular tone. This review outlines the current understanding of the vasomotor role of ROS in the vessels of the pulmonary and systemic circulations and considers the mechanisms of ROS effects on the functioning of vascular endothelial and smooth muscle cells in the perinatal and early postnatal periods.
Activity of many proteins and hence of the mechanisms of vascular tone regulation depend on medium acidity. A decrease of pH (in uncompensated acidosis) typically causes vasorelaxation of blood ...vessels, which is studied in sufficient detail in an adult organism. However, the effect of acidosis on the mechanisms of vascular tone regulation in the early postnatal period remains almost completely unexplored. The aim of this work was to study the effect of extracellular metabolic acidosis on the functional contribution of K
ATP
and TASK-1 potassium channels to vascular tone regulation in the early postnatal period. We modeled uncompensated extracellular metabolic acidosis (pH 6.8, equimolar NaHCO
3
substitution in a solution for NaCl) and studied isometric contractile responses of the saphenous artery in adult rats aged 3–4 months and rat pups aged 12–15 days. Arterial contraction to the α
1
-adrenergic agonist methoxamine at pH 6.8 was reduced compared to normal pH 7.4 in both 3–4-month- and 12–15-day-old rats. The K
ATP
channel blocker glibenclamide did not alter arterial responses to methoxamine at either pH 7.4 or pH 6.8 in both age groups. The TASK-1 channel blocker AVE1231 did not alter arterial contractile responses at any pH in 3–4-month-old rats. However, in 12–15-day-old rat pups, the AVE1231-induced increase in contractile responses to methoxamine was less at pH 6.8 than at pH 7.4. Thus, acidosis reduces arterial contractile activity in both 3–4-month-old rats and animals in early postnatal ontogenesis, while in the latter, the anticontractile role of TASK-1 channels decreases, and K
ATP
channels do not affect vascular tone regulation at either normal or acidic pH values in any of the age groups.
Our recent study showed that NO-mediated anticontractile effect of endothelium is absent in coronary arteries of adult rats, which suffered from antenatal/early postnatal hypothyroidism. This study ...tested the hypothesis that exercise training would improve such detrimental consequences of early thyroid deficiency.
Wistar dams received propylthiouracil (PTU, 7 ppm) in drinking water during gestation and two weeks postpartum; control dams received tap water. Six-week-old male offspring of control (CON) and PTU dams was divided into sedentary (CON-Sed, n = 12; PTU-Sed, n = 10) and trained (CON-Tr, n = 12; PTU-Tr, n = 10) groups; the latter had 24-h access to running wheels. Eight weeks later coronary arteries were studied by wire myography. Anticontractile effect of NO was assessed by the effects of NOS inhibitor L-NNA on the basal tone and contractile response to U46619. Oxidative phosphorylation complexes and eNOS were estimated by Western blotting.
T3/T4 and TSH levels (ELISA) were normalized in the progeny of PTU-treated dams at the age of 6 weeks and were not affected by training. Total running distance did not differ between CON-Tr and PTU-Tr. The contents of oxidative phosphorylation complexes were increased post-training in triceps brachii muscle from CON-Tr and PTU-Tr and in heart from PTU-Tr. Coronary arteries of PTU-Sed compared to CON-Sed demonstrated higher basal tone and contractile response to U46619, which were not further increased by L-NNA. The effects of L-NNA on the basal tone and contractile response to U46619 did not differ in CON-Tr and PTU-Tr groups, but were elevated in PTU-Tr compared to PTU-Sed group. PTU-Tr rats in comparison to PTU-Sed group had higher eNOS content in heart. Responses of coronary arteries to DEA/NO did not differ among all experimental groups.
Long-lasting coronary endothelial dysfunction resulted from transient thyroid deficiency during the antenatal/early postnatal period can be corrected by voluntary exercise training.
•Antenatal hypothyroidism weakens NO effects in coronary arteries of adult rats.•Exercise increases OXPHOS and eNOS in myocardium of previously hypothyroid rats.•Exercise improves anticontractile effects of NO in previously hypothyroid rats.
Aim
During early post‐natal development, arterial contraction depends less on Ca2+‐signalling pathways but more on changes in Ca2+‐sensitivity compared to adult animals. Whether this difference is ...related to Rho‐kinase, one of the major players affecting Ca2+‐sensitivity, is unknown for intact vessels. Thus, we tested the hypothesis that Rho‐kinase critically contributes to the higher Ca2+‐sensitivity of contraction in intact arteries of 1‐week‐old rats.
Methods
We studied 1‐week‐old, 4‐ to 5‐week‐old and 10‐ to 12‐week‐old rats performing isometric myography, Ca2+‐fluorimetry and Western blotting using intact saphenous arteries and arterial pressure measurements under urethane anaesthesia.
Results
In 10‐ to 12‐week‐old rats, methoxamine (MX) produced vasoconstriction associated with an increase in Ca2+i and Ca2+‐sensitivity. In contrast, in 1‐week‐old rats these contractions were accompanied only by an increase in Ca2+‐sensitivity. All MX‐induced effects were reduced by the Rho‐kinase inhibitor Y‐27632; this reduction was complete only in 1‐week‐old rats. The Rho‐kinase specific site Thr855 on MYPT1 was increasingly phosphorylated by MX in vessels of 1‐week‐old, but not 10‐ to 12‐week‐old rats; this effect was also inhibited completely by Y‐27632. The Rho‐kinase inhibitor fasudil in a dose not affecting the pressor response to MX in 4‐ to 5‐week‐old rats reduced it considerably in 1‐week‐old rats.
Conclusion
Our results suggest that the higher Ca2+‐sensitivity of arterial contraction in 1‐week‐old compared to 10‐ to 12‐week‐old rats is due to a greater Rho‐kinase activity. Constitutively active Rho‐kinase contributes to MX‐induced contraction in 10‐ to 12‐week‐old rats. In 1‐week‐old rats, additional Rho‐kinase activation is involved. This remodelling of the Rho‐kinase pathway is associated with its increased contribution to adrenergic arterial pressure responses.
The normal functioning of the vascular system in early ontogenesis can be altered by adverse exposures affecting the organism of the fetus/newborn during pregnancy, at birth, or in the postpartum ...period. However, the information on the “acute” (immediately after exposure) and “delayed” (after several days) effects of short-term (within several hours) perinatal normobaric hypoxia on the functioning of the peripheral vascular system of the systemic circulation in early ontogenesis in mammals is quite insufficient. The aim of this work was to study the “acute” and “delayed” single-session effects of a normobaric hypoxic exposure on the functioning of the systemic arteries in early postnatal ontogenesis. The contractile responses of the saphenous arteries in 10–14-day-old rats were studied in isometric mode. Acute normobaric hypoxia (8% O
2
) was simulated in 10-day-old rat pups for 2 h. The selected hypoxic regimen did not lead to changes in arterial contractile responses to the α
1
-adrenergic agonist methoxamine either immediately after exposure or several days later. Endothelium-dependent relaxation of the arteries to acetylcholine also did not differ between groups. Hypoxia did not change the contribution of anticontractile pathways associated with nitric oxide and Kv7 channels, as well as the procontractile role of Rho-kinase. Thus, short-term normobaric hypoxic exposure on postnatal day 10 leads to neither “acute” nor “delayed” changes in tone regulation of the peripheral arteries of the systemic circulation in the early postnatal period in rats.
The change in the diameter of small arteries and arterioles is a key mechanism for regulating the resistance of the vascular bed and blood pressure and blood flow in organs and tissues. The tone of ...arterial smooth muscle cells (SMC) depends on the level of membrane potential (MP), which, in turn, is determined by the balance of depolarizing and hyperpolarizing currents. The main hyperpolarizing current of SMC is the outward potassium current. Activation and opening of potassium channels counteract depolarization and inhibit calcium entry into the cell and contraction. Thus, potassium channels play an anticonstrictor role in the arteries. TASK-1 channels, members of the two-pore domain potassium channel family (K
2P
), have relatively recently been described in the vasculature. It is known that TASK-1 channels mediate outward potassium leakage current in arterial SMC. In addition, TASK-1 channels are regulated by a number of stimuli: their activity augments with an increase of extracellular pH, decreases in hypoxia, and can also change under the influence of inhalation/local anesthetics and vasoactive substances. TASK-1 channels play an important role in the regulation of arterial tone in pulmonary circulation; their dysfunction is one of the causes of arterial pulmonary hypertension development. In systemic arteries of adult animals, the influence of TASK-1 channels under normal pH is small or absent, but it can manifest itself under conditions of extracellular alkalosis. In addition, the anticontractile role of TASK-1 channels is more pronounced at the early stages of postnatal development. This review outlines the current understanding of the functional role and regulation of TASK-1 channels in the vascular system.
Aim
A decrease in the Ca2+ sensitivity of smooth muscle contraction is a hallmark of functional remodelling of blood vessels during development. However, the responsible factors are largely unknown. ...Here, we tested the hypothesis that the post‐natal decline of arterial Ca2+ sensitivity is the result of trophic effects of sympathetic nerves.
Methods
Contractile responses, intracellular Ca2+ levels and protein expression profiles were compared in saphenous arteries from young (1‐ and 2‐week‐old) and adult rats using wire myography, Ca2+ fluorimetry and Western blotting respectively.
Results
We observed a lower Ca2+ sensitivity of contractions induced by methoxamine, an agonist of α1‐adrenoceptors, and U46619, an agonist of thromboxane A2 receptors, in arteries from adult as compared to young animals. Post‐natal maturation was associated with stronger expression of regulatory proteins mediating Ca2+‐dependent contraction (myosin light chain kinase (MLCK), myosin targeting subunit (MYPT1) and h‐caldesmon) and weaker expression of proteins regulating Ca2+‐independent contraction (Rho kinase, extracellular‐regulated kinases (ERK1/2) and mitogen‐activated protein kinases p38 MAPK) in vessels from adult rats. To eliminate the trophic action of sympathetic nerves, we performed lumbar sympathectomy in adult rats. This resulted in higher Ca2+ sensitivity of agonist‐induced contractions in denervated as compared to control arteries. Furthermore, denervated arteries contained less MLCK, MYPT1 and h‐caldesmon and more ERK1/2 and p38 MAPK.
Conclusions
Sympathetic denervation reverses developmental changes both in Ca2+ sensitivity and in the expression of regulatory proteins back to the early post‐natal phenotype in the rat saphenous artery. We conclude that trophic effects of sympathetic nerves govern functional remodelling of arteries during early post‐natal development.
A decrease in the Ca(2+) sensitivity of smooth muscle contraction is a hallmark of functional remodelling of blood vessels during development. However, the responsible factors are largely unknown. ...Here, we tested the hypothesis that the post-natal decline of arterial Ca(2+) sensitivity is the result of trophic effects of sympathetic nerves.
Contractile responses, intracellular Ca(2+) levels and protein expression profiles were compared in saphenous arteries from young (1- and 2-week-old) and adult rats using wire myography, Ca(2+) fluorimetry and Western blotting respectively.
We observed a lower Ca(2+) sensitivity of contractions induced by methoxamine, an agonist of α1 -adrenoceptors, and U46619, an agonist of thromboxane A2 receptors, in arteries from adult as compared to young animals. Post-natal maturation was associated with stronger expression of regulatory proteins mediating Ca(2+) -dependent contraction (myosin light chain kinase (MLCK), myosin targeting subunit (MYPT1) and h-caldesmon) and weaker expression of proteins regulating Ca(2+) -independent contraction (Rho kinase, extracellular-regulated kinases (ERK1/2) and mitogen-activated protein kinases p38 MAPK) in vessels from adult rats. To eliminate the trophic action of sympathetic nerves, we performed lumbar sympathectomy in adult rats. This resulted in higher Ca(2+) sensitivity of agonist-induced contractions in denervated as compared to control arteries. Furthermore, denervated arteries contained less MLCK, MYPT1 and h-caldesmon and more ERK1/2 and p38 MAPK.
Sympathetic denervation reverses developmental changes both in Ca(2+) sensitivity and in the expression of regulatory proteins back to the early post-natal phenotype in the rat saphenous artery. We conclude that trophic effects of sympathetic nerves govern functional remodelling of arteries during early post-natal development.
During early post-natal development, arterial contraction depends less on Ca
-signalling pathways but more on changes in Ca
-sensitivity compared to adult animals. Whether this difference is related ...to Rho-kinase, one of the major players affecting Ca
-sensitivity, is unknown for intact vessels. Thus, we tested the hypothesis that Rho-kinase critically contributes to the higher Ca
-sensitivity of contraction in intact arteries of 1-week-old rats.
We studied 1-week-old, 4- to 5-week-old and 10- to 12-week-old rats performing isometric myography, Ca
-fluorimetry and Western blotting using intact saphenous arteries and arterial pressure measurements under urethane anaesthesia.
In 10- to 12-week-old rats, methoxamine (MX) produced vasoconstriction associated with an increase in Ca
and Ca
-sensitivity. In contrast, in 1-week-old rats these contractions were accompanied only by an increase in Ca
-sensitivity. All MX-induced effects were reduced by the Rho-kinase inhibitor Y-27632; this reduction was complete only in 1-week-old rats. The Rho-kinase specific site Thr
on MYPT1 was increasingly phosphorylated by MX in vessels of 1-week-old, but not 10- to 12-week-old rats; this effect was also inhibited completely by Y-27632. The Rho-kinase inhibitor fasudil in a dose not affecting the pressor response to MX in 4- to 5-week-old rats reduced it considerably in 1-week-old rats.
Our results suggest that the higher Ca
-sensitivity of arterial contraction in 1-week-old compared to 10- to 12-week-old rats is due to a greater Rho-kinase activity. Constitutively active Rho-kinase contributes to MX-induced contraction in 10- to 12-week-old rats. In 1-week-old rats, additional Rho-kinase activation is involved. This remodelling of the Rho-kinase pathway is associated with its increased contribution to adrenergic arterial pressure responses.
—
The production of reactive oxygen species (ROS) in skeletal muscle cells increases under contraction. Respiratory and locomotor muscles differ in contraction modes; therefore, ROS production and ...their effect on blood vessels in these functionally different types of muscles may differ. The aim of this work was to assess the role of ROS in the tone regulation of the diaphragm artery (
a. phrenica
) and deep brachial artery (
a. profunda brachii
) of the rat. The reactions of ring preparations of the arteries were studied in the isometric regimen. The NADPH oxidase (NOX) inhibitor VAS2870 caused relaxation of the preparations; the reaction magnitude of the diaphragm arteries was greater than that of the brachial arteries: at the VAS2870 concentration of 1 μM, the contraction force decreased to 33 and 91% of the precontraction level, respectively. Tiron (
scavenger) had a similar activity profile: at the concentration of 10 mM, it caused a decrease in the contraction force of the diaphragm arteries to 38% and of the brachial arteries to 66% of the initial contraction force. Catalase, which destroys H
2
O
2
, did not affect contraction of the diaphragm arteries at the concentration of 3000 U/mL but increased contraction of the deep brachial arteries. Using the method of quantitative polymerase chain reaction, it was shown that the mRNA content of
NOX
isoforms,
p22phox
,
p47phox
,
p67phox
,
Poldip2
,
Gpx-1
,
SOD-1
, and catalase in the tissue of two arteries does not differ, while the content of
SOD-3
mRNA in the diaphragm arteries is lower than in the brachial arteries. Thus,
produced by NOX greater increases tonic contraction of the diaphragm arteries than arteries of the locomotor muscle. H
2
O
2
, on the contrary, causes relaxation of the locomotor muscle arteries but not the diaphragm arteries. A relatively low level of
SOD-3
expression may be a reason for the pronounced effect of O
2–
in the diaphragm arteries.
