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).
Endothelial function plays an important role in the extrauterine adaptation of newborn infants. Endothelium produces different biologically active mediators, which play the central role in physiological and pathological processes and also in the extrauterine adaptation of newborn infants. The imbalance between vasoconstrictive and vasodilatation factors results in impaired cardiovascular adaptation and microcirculation and also brain injury. Microcirculatory disturbances are observed very often in preterm babies, who have a serious risk for perinatal brain injury and further neurodevelopment disabilities. Present chapter presents the pathogenetic role of vascular tone regulators of endothelial genesis in the formation of microcirculatory changes in preterm babies with a high risk of perinatal hypoxic encephalopathy.
- hypoxic encephalopathy
- preterm infants
- endothelial function
- nitric oxide
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, 2, 3, 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, 6, 7, 8, 9, 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 . In addition to prematurity, the hypoxic-ischemic 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, 13, 14, 15].
Uteroplacental ischemia and circulatory changes in maternal-fetal system are the main chain in formation intrauterine hypoxia and different perinatal pathologies [16, 17, 18]. Previous investigations confirmed the significant role of endothelial function in the formation of different pregnancy pathologies and birth defects [19, 20, 21, 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, 24, 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 . 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 . 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.
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
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 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 .
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 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 . 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, 41, 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, 44, 45, 46, 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, 41, 42, 43, 44, 45, 46, 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. 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.
The authors sincerely thank Science Development Foundation under the President of the Azerbaijan Republic for providing specific reagent kits (Grant SDF-2010-1(1)-40/28-M-2). We also thank the staff of the Clinical Biochemistry Laboratory of Azerbaijan Medical University for assistance with biomarker analysis.
Conflict of interest
The authors declare no conflict of interests.
Lees C, Marlow N, Arabin B, Bilardo CM, Brezinka C, Derks JB, et al. Perinatal morbidity and mortality in early-onset fetal growth restriction: Cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE). Ultrasound in Obstetrics & Gynecology. 2013; 42:400-408
Unterscheider J, Daly S, Geary MP, Kennelly MM, McAuliffe FM, O’Donoghue K, et al. Optimizing the definition of intrauterine growth restriction: The multicenter prospective PORTO study. American Journal of Obstetrics and Gynecology. 2013; 208(290):e1-e6
Bader D, Kugelman A, Boyko V, Levitzki O, Lerner-Geva L, Riskin A, et al. Risk factors and estimation tool for death among extremely premature infants; a national study. Pediatrics. 2010; 125:696-703
Mooney SS, Lee RM, Tong S, Brownfoot FC. Expectant management of severe preterm preeclampsia: A comparison of maternal and fetal indications for delivery. Journal of Maternal-Fetal and Neonatal Medicine. 2016; 29(23):1-6. DOI: 10.3109/14767058.2016.1147555
Baschat AA. Neurodevelopment following fetal growth restriction and its relationship with antepartum parameters of placental dysfunction. Ultrasound in Obstetrics & Gynecology. 2011; 37:501-514
Morsing E, Asard M, Ley D, Stjernqvist K, Marsal K. Cognitive function following intrauterine growth restriction and very preterm birth. Pediatrics. 2011; 127:874-882
Morsing E, Gustafsson P, Brodzki J. Lung function in children born after fetal growth restriction and very preterm birth. Acta Paediatrica. 2012; 101:48-54
Markestad T, Kaaresen PI, Rønnestad A, et al. Early death, morbidity, and need of treatment among extremely premature infants. Pediatrics. 2005; 115:1289
Schmidt B, Roberts RS, Davis PG, et al. Prediction of late death or disability at age 5 years using a count of 3 neonatal morbidities in very low birth weight infants. The Journal of Pediatrics. 2015; 167:982
Goldenberg RL, Gravett MG, Iams J, Papageorghiou AT, Waller SA, Kramer M, et al. The preterm birth syndrome: Issues to consider in creating a classification system. American Journal of Obstetrics and Gynecology. 2012; 206(2):113-118. DOI: 10.1016/j.ajog.2011.10.865
Kadhim HJ, Duchateau J, Sebire G. Cytokines and brain injury: Invited review. Journal of Intensive Care Medicine. 2008; 23:236-249
Malaeb S, Dammann O. Fetal inflammatory response and brain injury in the preterm newborn. Journal of Child Neurology. 2009; 24(9):1119-1126
Dammann O, Leviton A. Inflammatory brain damage in preterm newborns--dry numbers, wet lab, and causal inferences. Early Human Development. 2004; 79:1-15
Sciaky-Tamir Y, Hershkovitz R, Mazor M, Shelef I, Erez O. The use of imaging technology in the assessment of the fetal inflammatory response syndrome—Imaging of the fetal thymus. Prenatal Diagnosis. 2015; 35(5):413-419
Viscardi RM. Perinatal inflammation and lung injury. Seminars in Fetal & Neonatal Medicine. 2012 Feb; 17(1):30-35
Jeffrey S, Gilbert AJB, Gingery A, Chasson S. Circulating and utero-placental adaptations to chronic placental ischemia in the rat. Placenta. 2011; 33(2):100-105
Espinoza J. Uteroplacental ischemia in early- and late-onset pre-eclampsia: A role for the fetus? Ultrasound in Obstetrics & Gynecology. 2012; 40(4):373-382
Warrington J, Fan F, Murphy S, Roman R, Drummond H, Granger J, et al. Placental ischemia impairs cerebral blood flow autoregulation and increases blood-brain barrier permeability in pregnant rats. The FASEB Journal. 2015; 29(1 Supplement):646.7
Gilbert JS, Ryan MJ, LaMarca BB, Sedeek M, Murphy SR, Granger JP. Pathophysiology of hypertension during preeclampsia: Linking placental ischemia with endothelial dysfunction. American Journal of Physiology - Heart and Circulatory Physiology. 2008; 294(2):H541-H550
Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA. Pathophysiology of preeclampsia: Linking placental ischemia/hypoxia with microvascular dysfunction. Microcirculation. 2002; 9(3):147-160
Sanchez L, Prada CE, Riaño-Medina CE, Lopez M. Endothelial dysfunction and preeclampsia: Role of oxidative stress. Frontiers in Physiology. 2014; 5:372
Zárate A, Saucedo R, Valencia J, Manuel L, Hernández M. Early disturbed placental ischemia and hypoxia creates immune alteration and vascular disorder causing preeclampsia. Archives of Medical Research. 2014; 45(7):519-524
MacDonald JF, Xiong ZG, Jackson MF. Paradox of Ca2+ signaling, cell death and stroke. Trends in Neurosciences. 2006; 29:75-81
Executive summary. Neonatal encephalopathy and neurologic outcome, second edition. Report of the American College of Obstetricians and Gynecologists’ task force on neonatal encephalopathy. The Obstetrician and Gynaecologist. 2014; 123:896-901
O’Sullivan M. Leukoaraiosis. Practical Neurology. 2008; 8:26-38
Wassink G, Gunn ER, Drury PP, et al. The mechanisms and treatment of asphyxial encephalopathy. Frontiers in Neuroscience. 2014; 8:40
Peters A, Schweiger U, Pellerin L, et al. The selfish brain: Competition for energy resources. Neuroscience and Biobehavioral Reviews. 2004; 28:143-180
Martinez-Biarge M, Diez-Sebastian J, Wusthoff CJ, Mercuri E, Cowan FM. Antepartum and intrapartum factors preceding neonatal hypoxic-ischemic encephalopathy. Pediatrics. 2013; 132(4):e952-e959
Northington FJ, Chavez-Valdez R, Martin LJ. Neuronal cell death in neonatal hypoxia-ischemia. Annals of Neurology. 2011 May; 69(5):743-758
Hagberg H, Mallard C, Ferriero DM, Vannucci SJ, Levison SW, Vexler ZS, et al. The role of inflammation in perinatal brain injury. Nature Reviews Neurology. 2015; 11:192-208
Pham H, Duy AP, Pansiot J, Bollen B, Gallego J, Charriaut-Marlangue C, et al. Impact of inhaled nitric oxide on white matter damage in growth-restricted neonatal rats. Pediatric Research. 2015; 77(4):563-569
Ji H, Tan S, Igarashi J, et al. Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy. Annals of Neurology; 65(2):209-217
Lai M-C, San-Nan YJ. Perinatal hypoxic-ischemic encephalopathy. Journal of Biomedicine and Biotechnology. 2011; 2011:609813
Buschmann K, Tschada R, Metzger MS, Braach N, Kuss N, Hudalla H, et al. RAGE controls leukocyte adhesion in preterm and term infants. BMC Immunology. 2014; 15:53. DOI: 10.1186/s12865-014-0053-0
Nussbaum C, Gloning A, Pruenster M, Frommhold D, Bierschenk S, Genzel-Boroviczény O, et al. Neutrophil and endothelial adhesive function during human fetal ontogeny. Journal of Leukocyte Biology. 2013; 93(2):175-184
D'Alquen D, Kramer BW, Seidenspinner S, Speer CP. Activation of umbilical cord endothelial cells and fetal inflammatory response in preterm infants with chorioamnionitis and funisitis. Pediatric Research. 2005; 57(2):263-269
Liao JK. Linking endothelial dysfunction with endothelial cell activation. The Journal of Clinical Investigation. 2013; 123(2):540-541
Huseynova S, Panakhova N, Orujova P, Hasanov S, Guliyev M, Orujov A. Elevated levels of serum sICAM-1 in asphyxiated low birth weight newborns. Scientific Reports. 2014; 4:6850. DOI: 10.1038/srep06850
Huseynova SA, Panakhova NF, Hasanov SS, Guliyev MR. Nitric oxide synthase and neurodevelopmental disorders. In: Nitric Oxide Synthase. IntechOpen; 2016. ISBN 978-953-51-5012
Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of the role of intrapartum hypoxiaischemia in the causation of neonatal encephalopathy. American Journal of Obstetrics and Gynecology. 2008; 199(6):587-595
Azzopardi D. Clinical management of the baby with hypoxic ischaemic encephalopathy. Early Human Development. 2010; 86(6):345-350
Mercuri E, Guzzetta A, Haataja L, Cowan F, Rutherford M, Counsell S, et al. Neonatal neurological examination in infants with hypoxic ischaemic encephalopathy: Correlation with MRI findings. Neuropediatrics. 1999; 30(2):83-89
MacLennan AH, Thompson SC, Gecz J. Cerebral palsy: Causes, pathways, and the role of genetic variants. American Journal of Obstetrics and Gynecology. 2015; 213:779-788
Beken S, Aydın B, Dilli D, Erol S, Zenciroğlu A, Okumuş N. Can biochemical markers predict the severity of hypoxicischemic encephalopathy? The Turkish Journal of Pediatrics. 2014; 56(1):62-68
Northington FJ, Zelaya ME, O’Riordan DP, et al. Failure to complete apoptosis following neonatal hypoxia-ischemia manifests as “continuum” phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain. Neuroscience. 2007; 149(4):822-833
Volpe JJ. Neurology of the Newborn. 5th ed. Saunders; 2008. 1120 p
Vannucci RC, Towfighi J, Vannucci SJ. Secondary energy failure after cerebral hypoxia-ischemia in the immature rat. Journal of Cerebral Blood Flow and Metabolism. 2004; 24(10):1090-1097