**1. Introduction**

The largest research object of modern perinatology and neonatology is preterm and growth retarded children. Despite the rapid development of perinatal care and the early prevention of many pathologies, worldwide perinatal morbidity and mortality remain high [1–4].

The results of the scientific researches prove that perinatal pathologies play a leading role in the formation of illness, death, disability, social and biological disarray, and different types of neurodevelopmental disorders [5–10]. It is known that birth is a complicated biological process regulated by numerous signal molecules and biologically active substances. The fetal inflammatory response plays a major role in the pathogenesis of premature birth [11]. In addition to prematurity, the hypoxicischemic changes in feto-placental system can result in different perinatal pathologies, such as acute intraventricular bleeding, periventricular leukomalation, necrotic enterocolitis, bronchial lung dysplasia, myocardial dysfunction, sepsis, etc. [12–15].

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 microcirculatory and ischemic changes in preterm infants.

## **2. The pathophysiology of brain injury in hypoxic: ischemic encephalopathy (HIE)**

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

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

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

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**preterm infants**

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

followed by anaerobic metabolism with accumulation of lactic acid. With the restoration of blood flow, there is a brief period of normalization of cerebral metabolism called a latent period. The reperfusion is necessary for the recovery and stopping of processes leading to necrotic neuronal injury during the primary phase of injury. However when the brain has not recovered from the initial injury, the reperfusion can simultaneously cause additional (delayed) injury, and mitochondrial dysfunction continues. When cerebral ischemia is more acute and prolonged, especially in the result of accompanying pathological processes (infection, hereditary factors, environmental and other damaging factors), primary injury is followed by secondary injury, which is often characterized by subsequent resulting in more serious neurological and somatic disintegration in development [29]. Secondary injury is often associated with edema of the brain cells. Compensatory restoration of energy reactions is followed by the intracellular edema and by more complex inflammatory

Increased amount of free radicals and nitric oxide (NO), increased synthesis of nitric oxide synthase (NOS), activated intercellular adhesion, and apoptosis are the tightly connected chains of this pathological process (10–13). However it is confirmed that endothelial NOS (eNOS) genesis plays very important role in maintaining pulmonary blood flow and preventing pulmonary hypertension. Some experimental studies suggested that *inhibiting NOS could prevent further brain injury* [31]. Selective inhibition of NO of neuronal genesis is more promising in the direc-

The severity of inflammatory processes is correlated with the activation of different mediators, especially cytokines and adhesion molecules. These molecules cause to the migration of leukocytes to the inflammation center and compact adhesion of migrated leukocytes to vascular endothelium [34, 35]. The main stimulus factor for the synthesis of inflammatory mediators is the activation of endothelial cells of the fetus. Thus, endothelial dysfunction is the main factor that stimulates intracellular and vascular adhesion and leads to the activation of fetal leukocytes [36, 37].

There is much to be investigated how the inflammatory response to hypoxia is regulated and the complete role of different mediators as well as vasoregulatory, anti-inflammatory, and apoptosis molecules under physiological and pathological conditions is unknown. The goal of this chapter is to present the results of recent investigations about the role of vasoregulatory markers in the formation of microcirculatory disorders in hypoxic-ischemic encephalopathy of preterm infants.

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

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

response cascade with the presence of free oxygen radicals [30].

tion of pathogenetic treatment of HIE in newborn infants [31–33].

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

**Figure 1.** *The pathogenesis of hypoxic-ischemic encephalopathy [33].*

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

followed by anaerobic metabolism with accumulation of lactic acid. With the restoration of blood flow, there is a brief period of normalization of cerebral metabolism called a latent period. The reperfusion is necessary for the recovery and stopping of processes leading to necrotic neuronal injury during the primary phase of injury. However when the brain has not recovered from the initial injury, the reperfusion can simultaneously cause additional (delayed) injury, and mitochondrial dysfunction continues. When cerebral ischemia is more acute and prolonged, especially in the result of accompanying pathological processes (infection, hereditary factors, environmental and other damaging factors), primary injury is followed by secondary injury, which is often characterized by subsequent resulting in more serious neurological and somatic disintegration in development [29]. Secondary injury is often associated with edema of the brain cells. Compensatory restoration of energy reactions is followed by the intracellular edema and by more complex inflammatory response cascade with the presence of free oxygen radicals [30].

Increased amount of free radicals and nitric oxide (NO), increased synthesis of nitric oxide synthase (NOS), activated intercellular adhesion, and apoptosis are the tightly connected chains of this pathological process (10–13). However it is confirmed that endothelial NOS (eNOS) genesis plays very important role in maintaining pulmonary blood flow and preventing pulmonary hypertension. Some experimental studies suggested that *inhibiting NOS could prevent further brain injury* [31]. Selective inhibition of NO of neuronal genesis is more promising in the direction of pathogenetic treatment of HIE in newborn infants [31–33].

The severity of inflammatory processes is correlated with the activation of different mediators, especially cytokines and adhesion molecules. These molecules cause to the migration of leukocytes to the inflammation center and compact adhesion of migrated leukocytes to vascular endothelium [34, 35]. The main stimulus factor for the synthesis of inflammatory mediators is the activation of endothelial cells of the fetus. Thus, endothelial dysfunction is the main factor that stimulates intracellular and vascular adhesion and leads to the activation of fetal leukocytes [36, 37].

There is much to be investigated how the inflammatory response to hypoxia is regulated and the complete role of different mediators as well as vasoregulatory, anti-inflammatory, and apoptosis molecules under physiological and pathological conditions is unknown. The goal of this chapter is to present the results of recent investigations about the role of vasoregulatory markers in the formation of microcirculatory disorders in hypoxic-ischemic encephalopathy of preterm infants.
