CHILDREN BORN FROM WOMEN WITH PREECLAMPSIA HAVE ALTERATIONS IN CEREBRAL NEUROVASCULAR DEVELOPMENT AND A HIGH RISK FOR DEVELOPING COGNITIVE ALTERATIONS. BECAUSE CEREBRAL BLOOD VESSELS ARE CRITICAL COMPONENTS IN CEREBROVASCULAR DEVELOPMENT, WE EVALUATED THE BRAIN MICROVASCULAR PERFUSION AND MICROVASCULAR REACTIVITY (EXPOSED TO EXTERNAL STIMULI OF WARM AND COLD) IN PUPS BORN TO PREECLAMPSIA-LIKE SYNDROME BASED ON THE REDUCTION OF UTERINE PERFUSION (RUPP). ALSO, WE EVALUATE THE ANGIOGENIC PROTEOMIC PROFILE IN THOSE BRAINS. PREGNANT MICE SHOWED A REDUCTION IN UTERINE FLOW AFTER RUPP SURGERY (-40 TO 50%) ASSOCIATED WITH UNFAVORABLE PERINATAL RESULTS COMPARED TO SHAM MICE. FURTHERMORE, OFFSPRING OF THE RUPP MICE EXHIBITED REDUCED BRAIN MICROVASCULAR PERFUSION AT POSTNATAL DAY 5 (P5) COMPARED WITH OFFSPRING FROM SHAM MICE. THIS REDUCTION WAS PREFERENTIALLY OBSERVED IN FEMALES. ALSO, BRAIN MICROVASCULAR REACTIVITY TO EXTERNAL STIMULI (WARM AND COLD) WAS REDUCED IN PUPS OF RUPP MICE. FURTHERMORE, A DIFFERENTIAL EXPRESSION OF THE ANGIOGENIC PROFILE ASSOCIATED WITH INFLAMMATION, EXTRINSIC APOPTOTIC, CANCER, AND CELLULAR SENESCENCE PROCESSES AS THE PRIMARY SIGNALING IMPAIRED PROCESS WAS FOUND IN THE BRAINS OF RUPP-OFFSPRING. THEN, OFFSPRING (P5) FROM PREECLAMPSIA-LIKE SYNDROME EXHIBIT IMPAIRED BRAIN PERFUSION AND MICROVASCULAR REACTIVITY, PARTICULARLY IN FEMALE MICE, ASSOCIATED WITH DIFFERENTIAL EXPRESSION OF ANGIOGENIC PROTEINS IN THE BRAIN TISSUE.

EVIDENCE FROM CLINICAL STUDIES HAS PROPOSED THAT CHILDREN BORN FROM PREECLAMPTIC WOMEN HAVE A HIGHER RISK OF SUFFERING NEUROLOGICAL, PSYCHOLOGICAL, OR BEHAVIORAL ALTERATIONS. HOWEVER, TO DATE, THE MECHANISMS BEHIND THESE OUTCOMES ARE POORLY UNDERSTOOD. HERE, WE SPECULATE THAT THE NEURODEVELOPMENTAL ALTERATIONS IN THE CHILDREN OF PREECLAMPTIC PREGNANCIES RESULT FROM IMPAIRED ANGIOGENESIS. THE PRO-ANGIOGENIC FACTORS VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) AND PLACENTAL GROWTH FACTOR (PLGF) ARE KEY REGULATORS OF BOTH VASCULAR AND NEUROLOGICAL DEVELOPMENT, AND IT HAS BEEN WIDELY DEMONSTRATED THAT UMBILICAL BLOOD OF PREECLAMPTIC PREGNANCIES CONTAINS HIGH LEVELS OF SOLUBLE VEGF RECEPTOR TYPE 1 (SFLT-1), A DECOY RECEPTOR OF VEGF. AS A CONSEQUENCE, THIS ANTI-ANGIOGENIC STATE COULD LEAD TO LONG-LASTING NEUROLOGICAL OUTCOMES. IN THIS NON-SYSTEMATIC REVIEW, WE PROPOSE THAT ALTERATIONS IN THE CIRCULATING CONCENTRATIONS OF VEGF, PLGF, AND SFLT-1 IN PREECLAMPTIC PREGNANCIES WILL AFFECT BOTH FETAL CEREBROVASCULAR FUNCTION AND NEURODEVELOPMENT, WHICH IN TURN MAY CAUSE COGNITIVE ALTERATIONS IN POST-NATAL LIFE.

OBJECTIVES: TO COMPARE THE NEUROVASCULAR STRUCTURE AND PROTEIN EXPRESSION OF CEREBRAL ANGIOGENESIS MARKERS AS WELL AS MORPHOMETRIC AND HISTOLOGICAL VARIATIONS IN THE BRAIN OF CHILDREN OF MOTHERS WITH AND WITHOUT HYPERTENSIVE DISORDER OF PREGNANCY. METHODS: AN ANALYTICAL OBSERVATIONAL STUDY OF CASES AND CONTROLS, RETROSPECTIVE, WITH DOUBLE, RANDOM, AND BLINDED READING OF HISTOLOGICAL SAMPLES, OF BRAINS FROM THE PRODUCTS OF PREGNANCIES WITH AND WITHOUT HYPERTENSIVE DISEASES OF PREGNANCY THAT REST IN THE ARCHIVES OF THE HOSPITAL UNIVERSITARIO SAN IGNACIO. RESULTS: THE PROJECT IS ONGOING. TO DATE, THE HISTOLOGICAL STRUCTURE OF 17 CASES HAS BEEN REVIEWED IN HEMATOXYLIN-EOSIN. THE PRESENCE OF RED NEURONS, AREAS OF HEMORRHAGE, AREAS OF RECENT AND OLD INFARCTION AS WELL AS THE PRESENCE OF CALCIFICATIONS IN THE CORTEX, HIPPOCAMPUS, AND CEREBELLUM HAVE BEEN LOOKED FOR AND DOCUMENTED. CONCLUSION: OUR KNOWLEDGE OF THE PREECLAMPSIA IMPACT ON THE DEVELOPMENT OF THE FETUS IS STILL LIMITED. STUDIES LIKE OURS WANT TO HELP TO UNDERSTAND THE INTRAUTERINE ENVIRONMENT AND ITS CONSEQUENCES.

BACKGROUND: CEREBRAL COMPLICATIONS IN PREECLAMPSIA ARE LEADING CAUSES OF MATERNAL MORTALITY WORLDWIDE BUT PATHOPHYSIOLOGY IS LARGELY UNKNOWN AND A CHALLENGE TO STUDY. USING AN IN VITRO MODEL OF THE HUMAN BLOOD-BRAIN BARRIER (BBB), WE EXPLORED THE ROLE OF VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2 (VEGFR2) IN PREECLAMPSIA. METHODS: THE HUMAN BRAIN ENDOTHELIAL CELL LINE (HCMEC/D3) CULTURED ON TRANWELLS INSERT WAS EXPOSED (12 HOURS) TO PLASMA FROM WOMEN WITH PREECLAMPSIA (N = 28), NORMAL PREGNANCY (N = 28), AND NONPREGNANT (N = 16) CONTROLS. TRANSENDOTHELIAL ELECTRICAL RESISTANCE (TEER) AND PERMEABILITY TO 70 KDA FLUORESCEIN ISOTHIOCYANATE (FITC)-DEXTRAN WERE MEASURED FOR THE ASSESSMENT OF BBB INTEGRITY. WE EXPLORED POSSIBLE UNDERLYING MECHANISMS, WITH A FOCUS ON THE EXPRESSION OF TIGHT JUNCTION PROTEINS AND PHOSPHORYLATION OF 2 TYROSINE RESIDUES OF VEGFR2, ASSOCIATED WITH VASCULAR PERMEABILITY AND MIGRATION (PY951) AND CELL PROLIFERATION (PY1175). PLASMA CONCENTRATIONS OF SOLUBLE FMS-LIKE TYROSINE KINASE-1 (SFLT-1) AND PLACENTAL GROWTH FACTOR (PLGF) WERE ALSO MEASURED. RESULTS: HCMEC/D3 EXPOSED TO PLASMA FROM WOMEN WITH PREECLAMPSIA EXHIBITED REDUCED TEER AND INCREASED PERMEABILITY TO 70 KDA FITC-DEXTRAN. THESE CELLS UPREGULATED THE MESSENGER RIBONUCLEIC ACID (MRNA) LEVELS OF VEGFR2, AND PY951-VEGFR2, BUT REDUCED PY1175-VEGFR2 (P < 0.05 IN ALL CASES). NO DIFFERENCE IN MRNA EXPRESSION OF TIGHT JUNCTION PROTEIN WAS OBSERVED BETWEEN GROUPS. THERE WAS NO CORRELATION BETWEEN ANGIOGENIC BIOMARKERS AND BBB PERMEABILITY. CONCLUSIONS: WE PRESENT A PROMISING IN VITRO MODEL OF THE BBB IN PREECLAMPSIA. SELECTIVE TYROSINE PHOSPHORYLATION OF VEGFR2 MAY PARTICIPATE IN THE INCREASED BBB PERMEABILITY IN PREECLAMPSIA IRRESPECTIVE OF PLASMA CONCENTRATIONS OF ANGIOGENIC BIOMARKERS.