A New Concept of the Pathogenesis of Retinopathy of Prematurity

The lecture provides a detailed description of the development of retinal vessels, vasculogenesis and angiogenesis. The cascade of protective mechanisms of the organism of the system of combating hyperoxia, the system of combating circulatory hypoxia and the key growth factors of the vascular endothelium during angiogenesis are shown. The pathogenesis of retinopathy of prematurity is described and the first phase of ROP development is analyzed in detail, the reasons for the delay in the maturation of vascular autoregulation are explained. The author proposed to distinguish the first preclinical phase in the ROP classification. In contrast to the modern concentration of attention of ophthalmologists on the active and cicatricial stages, the author proposes to pay special attention to the study of the preclinical stage of ROP, where its pathogenesis is formed.

MORPHOLOGICAL CHARACTERISTICS OF VASCULAR-STROMAL REMODELING OF HUMAN PLACENTA VILLOUS CHORION IN CONDITIONS OF CIRCULATORY HYPOXIA

Цель - изучение микроструктурных особенностей, ангиогенных и сосудисто-стромальных иммуногистохимических маркеров ремоделирования ворсин плаценты в условиях циркуляторной гипоксии различной степени тяжести. Материал и методы. Проведено гистологическое, иммуногистохимическое исследование тканей 54 плацент при доношенной беременности. Из них - 20 плацент - от женщин, у которых беременность протекала на фоне неоперированного врожденного порока сердца (ВПС); 19 плацент - при корригированном ВПС и 15 - при физиологическом течении беременности и родов (контроль). Во фрагментах плацентарной ткани проводили реакции с моноклональными мышиными антителами к VEGF, CD34, SMA, Collagen III, Collagen IV. Результаты. В работе представлены гистологическое строение ворсинчатого хориона при физиологически протекающей беременности, а также структурные особенности компенсаторно-приспособительных реакций плаценты в ответ на гипоксический стресс. Количественная оценка экспрессии сигнальных белковых молекул, участвующих в ремоделировании плацентарного барьера, выявила зависимость структурно-функциональной перестройки ворсин плаценты с учетом наличия гипоксемии у беременной женщины и степени ее выраженности. Установлены структурно-функциональные маркеры дезадаптации ворсинчатого хориона в условиях некорригированной циркулятоной гипоксемии, обусловленной ВПС. Отмечена активация компенсаторно-приспособительных процессов в плаценте при снижении гипоксемии у беременной с хирургической коррекцией порока сердца. Выводы. Компенсаторно-приспособительные процессы в плаценте, адекватный уровень репарации поврежденных плацентарных тканей являются необходимым условием физиологического течения беременности и родов. Нарушение процессов структурно-функционального ремоделирования ворсинчатого хориона в условиях циркуляторной гипоксии способствует развитию фетоплацентарной недостаточности, служит фактором риска перинатальной патологии плода и новорожденного. Адаптивная перестройка неоангиогенеза и экстрацеллюлярного матрикса ворсин плаценты способствует пролонгированию гестации, рождению живого, доношенного ребёнка. Objective - to study microstructural characteristics, angiogenic and vascular-stromal immunohistochemical markers of remodeling in the villous chorion of placenta in conditions of circulatory hypoxia of various severity levels. Material and methods. Histological and immunohistochemical study of the 54 term placentas was carried out. Twenty placentas were obtained from women suffering from non-operated CHD; 19 placentas - from women with corrected CHD and 15 - from women with normal pregnancy and delivery (controls). Monoclonal mouse antibodies raised against VEGF, CD34, SMA, Collagen III, and Collagen IV were used to carry out immunohistochemical reaction in specimens of placental tissue. Results. The paper demonstrated the histological structure of the chorionic villi obtained from women with normal pregnancy and structural characteristics of compensatory and adaptive response of placenta to hypoxic stress. The quantitative assessment of the expression of signaling protein molecules involved in the remodeling of the placental barrier demonstrated that the structural and functional restructuring of placental villi depended on hypoxemia and its intensity in pregnant women. Markers of structural and functional deadaptation of the chorionic villi in conditions of uncorrected circulation hypoxia caused by CHD were established. The signs of placental compensatory-adaptive processes activation in cases of surgical correction of the heart defect before pregnancy were identified. Conclusions. The compensatory and adaptive processes in placenta and adequate level of reparation of damaged placental tissues are vital condition of physiological course of pregnancy and childbirth. The violation of structural and functional remodeling of villous chorion in conditions of circulatory hypoxia contributes to the development of placental insufficiency, increases the risk of perinatal pathology of the fetus and the newborn. Adaptive remodeling of neoangiogenesis and extracellular matrix of placental villi contributes to gestation prolonging and live full-time birth.

Congenital heart defects and pregnancy: current view on the mechanisms of placental adaptation to circulatory hypoxia

In this review, we perform clinical and morphological analysis of the mechanisms underlying adaptation of the human placenta to hypoxia in the fetoplacental complex in pregnant women with congenital heart defects (CHDs). We assessed specific characteristics of macroscopic and microscopic structure of the placenta in women with this extragenital pathology. We descried morphological involutive dystrophic and compensatory mechanisms that develop in the placenta of women with impaired hemodynamics. We proposed molecular markers, whose investigation will clarify functional state of the placental barrier and ways of remodeling vascular-stromal components of the villous chorion. Potential risks associated with circulatory hypoxia in the mother-placenta-fetus system should be taken into account in the management of pregnant women with CHDs. Detection of placental maladaptation signs in mothers with CHDs will help to identify the risk group of newborns, organize preventive therapy, prophylaxis of diseases, health improvement, and treatment of newborns. Key words: compensatory and adaptive processes, hypoxia, immunohistochemistry, morphology, placenta

Correction of hypoxic state by metabolic precursors of endogenous activator of mitochondrial ATP-dependent K+channels

Aim. The antihypoxic properties of uridine and uridine-5'-monophosphate (UMP), which are the metabolic precursors of the natural activator of mitochondrial ATP-dependent K+ channels (mitoKATP channels) uridine diphosphat were investigated on the models of hypoxic hypoxia with hypercapnia (HHH), hemic hypoxia and local circulatory hypoxia. Methods. HHH was created in males and females white mice weighing 28-30 g. The animals were placed one by one in hermetically closed container and the duration of their life was determined. The antihypoxic activity of the substances was compared with the reference anthypoxant amtizole (50 mg/kg). Hemic hypoxia was caused in Wistar rats weighing 350-370 g by the injection of sodium nitrite (intramuscularly, 100 mg/kg). Uridine or UMP 30 mg/kg was injected intraperitoneally 30 minutes before the onset of HHH and hemic hypoxia. Local circulatory hypoxia was modeled in male Wistar rats weighing 250-300 g. Acute coronary occlusion lasting 60 min was reproduced by legation of descending branch of the left coronary artery (LCA). Uridine or UMP (30 mg/kg) was administered intravenously 5 minutes prior to LCA occlusion. Selective blocker of mitoKATP channels 5-hydroxydecanoate (5 mg/kg, intravenously, 5 minutes prior uridine or UMP) was used to determine the role of these channels in the mechanism of antihypoxic action of the studied drugs. The volume of the damaged myocardium was used as the marker of antihypoxic activity of uridine and UMP. Results. Different resistance to hypoxia in female and male mice was observed in HHH. The female mice were more resistant, their life duration was 43% more than the males. Uridine and UMP displayed antihypoxic activity only in male mice, increasing their life duration by 25% and 20% respectively. This effect was 2 times less than that of amtisol. In similar conditions in females mice the preparations did not show a protective effect. In hemic hypoxia the life duration of rats treated with uridine and UMP did not differ from the control values. Circulatory hypoxia, caused by occlusion of the LCA, led to the formation of a local zone of myocardial damage. Uridine or UMP decreased the damage zone in 2 and 3,5 times respectively. The inhibitor of mitoKATP channels blocked the protective effect of these compounds. Conclusion. Uridine and UMP have a distinct antihypoxic effect in HHH and a marked protective effect in local circulatory hypoxia. The antihypoxic activity of druges in HHH is manifested differently in female and male mice. It may be due to sexual differences in the resistance to hypoxia. The maximum effect is observed in male who have initially low resistance to oxygen deficiency. The mechanism of the protective action of uridine and UMP in the circulatory hypoxia is associated with the activation of mitoKATP channels.