**3. Endothelial dysfunction and microcirculatory disorders in HIE of preterm infants**

Several clinical and experimental studies confirmed the role of endothelial dysfunction in the pathogenesis of hypoxic-ischemic brain injury. The prospective clinical trial of Azerbaijan Medical University Neonatology group (ACTRN12612000342819) determined that the eNOS activity is declined in the background of increased NO concentrations depending on the severity of HIE [38].

The aim of the same study was also to study of the peripheral blood concentrations of vasoregulatory mediators of endothelial genesis in the pathogenesis of microcirculatory changes in newborn children with the birth asphyxia. It investigated 240 preterm infants with a high risk of HIE during early neonatal period. The main groups of children were classified into four groups depending on the degree of the microcirculation changes. The first group included preterm infants without microcirculatory changes of the body. The children with mild-degree microcirculatory disorders (continued less than 1 day and self-regenerating

*Basic and Clinical Understanding of Microcirculation*

tory and ischemic changes in preterm infants.

**encephalopathy (HIE)**

**2. The pathophysiology of brain injury in hypoxic: ischemic** 

complicated in preterm babies than mature children [23–25].

major factors that aggravate their course [26, 27].

Adaptation of the child to the extrauterine life significantly depends on the morpho-functional maturity of the organism, and it is more intense and more

The progress of all complicated pathophysiologic processes occurring in the newborn after birth significantly depends on cardiorespiratory adaptation [23, 24]. The changes in the cardiovascular and respiratory functions in the body related to the primarily changes in the microcirculation [25]. Microcirculatory changes are not only clinical symptoms of various pathologies of perinatal period but also one of the

HIE is one of the most serious birth complications accompanying with microcirculatory changes of different severity [28]. The pathogenesis of vascular changes in preterm infants is quite complicated and involves series of biochemical and molecular reactions (**Figure 1**). Persistent membrane depolarization results in excessive presynaptic glutamate release which follows with a series of cellular changes. The activation of NMDA receptors stimulates profound Ca2+ influx, which mediates cascades to cell death. *Primary energy failure* associated with the depletion of oxygen prevents oxidative phosphorylation, and the disrupting Na-K pump activity is

Uteroplacental ischemia and circulatory changes in maternal-fetal system are the main chain in formation intrauterine hypoxia and different perinatal pathologies [16–18]. Previous investigations confirmed the significant role of endothelial function in the formation of different pregnancy pathologies and birth defects [19–22]. The pathogenetic mechanisms of the formation of endothelial dysfunction during uteroplacental ischemia have not yet been investigated. Present chapter explores the role of vascular tone regulators of endothelial genesis in formation of microcircula-

**126**

**Figure 1.**

*The pathogenesis of hypoxic-ischemic encephalopathy [33].*

peroral and acrocyanosis, capillary refilling time duration less than 3 s) were included in the second group. The third group consisted of children with moderate microcirculatory disorders (such as peroral and acrocyanosis, marbling of the skin, capillary refilling time up to 7 s and continuing from 1 day up to 3 days). The fourth group consisted of children with severe microcirculatory disorders (acute peroral and acrocyanosis, marbling of the skin continuing more than 3 days, capillary refilling time with the duration of more than 7 s and continuing more than 3 days). The parameters were compared with the data of 2 control groups, which consisted of infants without perinatal and neonatal pathologies: 22 healthy preterm infants were included in control 1 and 30 healthy term infants in control 2.

Depending on the magnitude of the microcirculatory defects, the levels of vasoregulatory markers included in the study is shown in **Table 1**. The statistically significant reduction in eNOS activity in the first few days of life is noticeable, depending on the degree of severity of the microcirculatory disturbances. However toward the end of the early neonatal period in mild and moderate group children, eNOS concentrations significantly increased compared with children with severe microcirculatory changes and control groups.

As shown in **Table 1**, during severe microcirculation defects, NO synthesis of vascular endothelium remains at very low levels. In contrast, NO levels in the early days of the neonatal period were noted to significantly increase in infants with severe microcirculatory disturbances, and in the dynamics of the neonatal period, regardless of the microcirculatory changes severity, it is observed the increase of NO concentrations. At the same time, vasoconstrictor endothelin-1 levels rise during mild and moderate grades of microcirculation changes, while in infants with severe changes, it is reduced. This also proves once again that severe microcirculation disturbances lead to a violation of blood supply both in peripheral and vital organs during acute brain damage. We suggest that the lack of adequate levels of endothelin-1 synthesis, which is vasoconstrictor mediator of vascular endothelium in addition to decreased endothelial NOS activity, becomes one of the main points in the pathophysiology of HIE in preterm infants.

The follow-up results of these children included in this study identified significant relationships between peripheral endothelial vasoregulatory markers in the perinatal period and the formation of developmental disorders at an early age [39]. It was found that, in the presence of high concentrations of NO, early eNOS activity was insufficient in infants with moderate-to-severe neurodevelopmental disorders compared to neonates with mild neurologic changes or without evidence of neurological impairment (**Table 2**). These findings suggest that depressed eNOS activity and increased non-endothelial NO synthesis play also important roles in the formation of developmental impairments.

It is known that there is a disturbance of vasoregulation in the pathogenesis of various pathologies of the HIE and prenatal period [40–42]. Depending on the complexity of the pathological process and the degree of morphologic and functional immaturity of the body, hypoxic-ischemic lesions can lead to generalized system damage from mild to generalized severe dysfunctions and changes [43–47]. Acceleration of blood supply to vital organs during HIE is accompanied by peripheral vasospasm. However, the depletion of vascular tone's regulating mechanisms during the severe and long-lasting processes leads to the tissue hypoxia and acidosis [40–47]. This often leads to changes in vital organs, especially in brain tissue whose results are with changes that cannot be restored.

It is considered that statistically significant increase of NO levels in peripheral blood circulation during severe hypoxic changes is due to the exhaustion of endothelial NOS sources and the activation of non-endothelial NO synthesis sources.

**129**

**Table 1.**

*# - Control 1, ^ - Control 2 infants).*

*The Role of Vasoregulatory Markers in the Formation of Microcirculatory Changes in Premature…*

It is likely that in high endothelin-1 levels in children, mild and moderate changes are likely to compensate for an increase in peripheral vein tone and vital organs to maintain normal blood circulation. Reduced vasoconstrictor endothelium-1 levels in children with severe HIE symptoms are likely to be associated with decreased vascular tone and tissue hypoperfusion. In conclusion, the changes of capillary blood circulation in the result of endothelial dysfunction have the main role in the

*The level of vasoregulatory indicators in microcirculatory disturbances in children with HIE risk (p<0,05 in comparison with children with 0-none of, 1- mild, 2-moderate, 3-severe microcirculatory changes, and with* 

pathogenesis of hypoxic-ischemic inflammation in preterm infants.

*DOI: http://dx.doi.org/10.5772/intechopen.89910*

*The Role of Vasoregulatory Markers in the Formation of Microcirculatory Changes in Premature… DOI: http://dx.doi.org/10.5772/intechopen.89910*


**Table 1.**

*Basic and Clinical Understanding of Microcirculation*

microcirculatory changes and control groups.

in the pathophysiology of HIE in preterm infants.

formation of developmental impairments.

results are with changes that cannot be restored.

in control 2.

peroral and acrocyanosis, capillary refilling time duration less than 3 s) were included in the second group. The third group consisted of children with moderate microcirculatory disorders (such as peroral and acrocyanosis, marbling of the skin, capillary refilling time up to 7 s and continuing from 1 day up to 3 days). The fourth group consisted of children with severe microcirculatory disorders (acute peroral and acrocyanosis, marbling of the skin continuing more than 3 days, capillary refilling time with the duration of more than 7 s and continuing more than 3 days). The parameters were compared with the data of 2 control groups, which consisted of infants without perinatal and neonatal pathologies: 22 healthy preterm infants were included in control 1 and 30 healthy term infants

Depending on the magnitude of the microcirculatory defects, the levels of vasoregulatory markers included in the study is shown in **Table 1**. The statistically significant reduction in eNOS activity in the first few days of life is noticeable, depending on the degree of severity of the microcirculatory disturbances. However toward the end of the early neonatal period in mild and moderate group children, eNOS concentrations significantly increased compared with children with severe

As shown in **Table 1**, during severe microcirculation defects, NO synthesis of vascular endothelium remains at very low levels. In contrast, NO levels in the early days of the neonatal period were noted to significantly increase in infants with severe microcirculatory disturbances, and in the dynamics of the neonatal period, regardless of the microcirculatory changes severity, it is observed the increase of NO concentrations. At the same time, vasoconstrictor endothelin-1 levels rise during mild and moderate grades of microcirculation changes, while in infants with severe changes, it is reduced. This also proves once again that severe microcirculation disturbances lead to a violation of blood supply both in peripheral and vital organs during acute brain damage. We suggest that the lack of adequate levels of endothelin-1 synthesis, which is vasoconstrictor mediator of vascular endothelium in addition to decreased endothelial NOS activity, becomes one of the main points

The follow-up results of these children included in this study identified significant relationships between peripheral endothelial vasoregulatory markers in the perinatal period and the formation of developmental disorders at an early age [39]. It was found that, in the presence of high concentrations of NO, early eNOS activity was insufficient in infants with moderate-to-severe neurodevelopmental disorders compared to neonates with mild neurologic changes or without evidence of neurological impairment (**Table 2**). These findings suggest that depressed eNOS activity and increased non-endothelial NO synthesis play also important roles in the

It is known that there is a disturbance of vasoregulation in the pathogenesis of various pathologies of the HIE and prenatal period [40–42]. Depending on the complexity of the pathological process and the degree of morphologic and functional immaturity of the body, hypoxic-ischemic lesions can lead to generalized system damage from mild to generalized severe dysfunctions and changes [43–47]. Acceleration of blood supply to vital organs during HIE is accompanied by peripheral vasospasm. However, the depletion of vascular tone's regulating mechanisms during the severe and long-lasting processes leads to the tissue hypoxia and acidosis [40–47]. This often leads to changes in vital organs, especially in brain tissue whose

It is considered that statistically significant increase of NO levels in peripheral blood circulation during severe hypoxic changes is due to the exhaustion of endothelial NOS sources and the activation of non-endothelial NO synthesis sources.

**128**

*The level of vasoregulatory indicators in microcirculatory disturbances in children with HIE risk (p<0,05 in comparison with children with 0-none of, 1- mild, 2-moderate, 3-severe microcirculatory changes, and with # - Control 1, ^ - Control 2 infants).*

It is likely that in high endothelin-1 levels in children, mild and moderate changes are likely to compensate for an increase in peripheral vein tone and vital organs to maintain normal blood circulation. Reduced vasoconstrictor endothelium-1 levels in children with severe HIE symptoms are likely to be associated with decreased vascular tone and tissue hypoperfusion. In conclusion, the changes of capillary blood circulation in the result of endothelial dysfunction have the main role in the pathogenesis of hypoxic-ischemic inflammation in preterm infants.


#### **Table 2.**

*Blood concentrations of vasoregulatory markers in the early neonatal period by study groups. 1st group: HIE infants diagnosed with moderate-to-severe neurodevelopmental disorders or cerebral palsy; 2nd group: HIE infants with mild neurologic changes at an early age; 3rd group: HIE infants without evidence of neurological impairment in the post-neonatal period; control group: healthy preterm infants. a p<0,05 is considered statistically significant between main groups (1-2, 1-3, 2-3), and between main and control groups (1-c, 2-c, 3-c).*
