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Differences in placental capillary shear stress in fetal growth restriction may affect endothelial cell function and vascular network formation.

ABSTRACT: Fetal growth restriction (FGR) affects 5-10% of pregnancies, leading to clinically significant fetal morbidity and mortality. FGR placentae frequently exhibit poor vascular branching, but the mechanisms driving this are poorly understood. We hypothesize that vascular structural malformation at the organ level alters microvascular shear stress, impairing angiogenesis. A computational model of placental vasculature predicted elevated placental micro-vascular shear stress in FGR placentae (0.2?Pa in severe FGR vs 0.05?Pa in normal placentae). Endothelial cells cultured under predicted FGR shear stresses migrated significantly slower and with greater persistence than in shear stresses predicted in normal placentae. These cell behaviors suggest a dominance of vessel elongation over branching. Taken together, these results suggest (1) poor vascular development increases vessel shear stress, (2) increased shear stress induces cell behaviors that impair capillary branching angiogenesis, and (3) impaired branching angiogenesis continues to drive elevated shear stress, jeopardizing further vascular formation. Inadequate vascular branching early in gestation could kick off this cyclic loop and continue to negatively impact placental angiogenesis throughout gestation.

SUBMITTER: Tun WM

PROVIDER: S-EPMC6614400 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Differences in placental capillary shear stress in fetal growth restriction may affect endothelial cell function and vascular network formation.

Tun Win M WM Yap Choon Hwai CH Saw Shier Nee SN James Joanna L JL Clark Alys R AR

Scientific reports 20190708 1

Fetal growth restriction (FGR) affects 5-10% of pregnancies, leading to clinically significant fetal morbidity and mortality. FGR placentae frequently exhibit poor vascular branching, but the mechanisms driving this are poorly understood. We hypothesize that vascular structural malformation at the organ level alters microvascular shear stress, impairing angiogenesis. A computational model of placental vasculature predicted elevated placental micro-vascular shear stress in FGR placentae (0.2 Pa i ...[more]

PMID: 31285454

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Project description:BackgroundPosttranslational modification of histone tails such as histone 3 lysine 27 acetylation (H3K27ac) is tightly coupled to epigenetic regulation of gene expression. To explore whether this is involved in placenta pathology, we probed genome-wide H3K27ac occupancy by chromatin immunoprecipitation sequencing (ChIP-seq) in healthy placentas and placentas from pathological pregnancies with fetal growth restriction (FGR). Furthermore, we related specific acetylation profiles of FGR placentas to gene expression changes.ResultsAnalysis of H3K27ac occupancy in FGR compared to healthy placentas showed 970 differentially acetylated regions distributed throughout the genome. Principal component analysis and hierarchical clustering revealed complete segregation of the FGR and control group. Next, we identified 569 upregulated genes and 521 downregulated genes in FGR placentas by RNA sequencing. Differential gene transcription largely corresponded to expected direction based on H3K27ac status. Pathway analysis on upregulated transcripts originating from hyperacetylated sites revealed genes related to the HIF-1-alpha transcription factor network and several other genes with known involvement in placental pathology (LEP, FLT1, HK2, ENG, FOS). Downregulated transcripts in the vicinity of hypoacetylated sites were related to the immune system and growth hormone receptor signaling. Additionally, we found enrichment of 141 transcription factor binding motifs within differentially acetylated regions. Of the corresponding transcription factors, four were upregulated, SP1, ARNT2, HEY2, and VDR, and two downregulated, FOSL and NR4A1.ConclusionWe demonstrate a key role for genome-wide alterations in H3K27ac in FGR placentas corresponding with changes in transcription profiles of regions relevant to placental function. Future studies on the role of H3K27ac in FGR and placental-fetal development may help to identify novel targets for therapy of this currently incurable disease.

Project description:BackgroundThe reactive hyperemia index (RHI), which is obtained from the measurement of peripheral arterial tonometry (PAT), is highly associated with the percentage change in the end-diastolic arterial diameter (%flow-mediated dilatation) at reactive hyperemia. Low RHI is reported to be a mortality risk in patients with a high risk of cardiovascular (CV) disease. CV events are thought to be induced by physical and mental stress, including long-term fatigue and lack of sleep. However, the relationship between fatigue, lack of sleep, and endothelial function has not yet been established.MethodsHealthy hospital workers (n = 13, 6 men and 7 women) with an average age of 31.6 years were assigned to this study after they provided written informed consent. During the study period, we conducted 72 measurements of reactive hyperemia-peripheral arterial tonometry (RH-PAT) in the morning before or after their duty. At each measurement of the RH-PAT, we recorded the participants' hours of sleep and evaluated their degree of fatigue using a visual analog scale (VAS).ResultsAlthough the VAS was significantly less (36 ± 16% and 64 ± 12%, p < 0.001) and the hours of sleep were longer (6.0 ± 1.1 h and 2.3 ± 1.0 h, p < 0.001) before duty compared to those after duty, the RHI was comparable between them (2.12 ± 0.53 vs. 1.97 ± 0.50, p = 0.21). The VAS score was significantly higher in participants with low RHI (< 1.67) than in those with normal RHI (≥ 2.07) (59 ± 13% and 46 ± 21%, respectively, p < 0.05). However, binary logistic regression showed no significant association between low RHI and the VAS when adjusted for systemic blood pressure (SBP) and heart rate variability (HRV). In a simple regression analysis, the RHI was significantly correlated with the VAS score but not with sleep duration. A multiple linear regression analysis also showed no significant association between the RHI and VAS scores after adjustment for SBP and HRV.ConclusionsVascular endothelial function was not associated with overnight duty, hours of sleep, or degree of fatigue in healthy young adults. Since the RHI may be decreased in severe fatigue conditions through autonomic nerve activity, one should consider the physical and mental conditions of the examinee when evaluating the RH-PAT results.

Dataset Information

Differences in placental capillary shear stress in fetal growth restriction may affect endothelial cell function and vascular network formation.

Publications

Differences in placental capillary shear stress in fetal growth restriction may affect endothelial cell function and vascular network formation.

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