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Development of the blood-brain barrier within the paraventricular nucleus of the hypothalamus: influence of fetal glucocorticoid excess.

Frahm KA, Tobet SA - Brain Struct Funct (2014)

Bottom Line: Fetal dex exposure resulted in decreased blood vessel density within the PVN at P20.In the CTX, dex exposure increased BBB competency, in contrast to the PVN where there was a decrease in BBB competency and increased pericyte presence.Overall, unique alterations in the functioning of the BBB within the PVN may provide a novel mechanism for fetal antecedent programming that may influence adult disorders.

View Article: PubMed Central - PubMed

Affiliation: Program in Cell and Molecular Biology, Colorado State University, 1617 Campus Delivery, Fort Collins, CO, 80523-1617, USA.

ABSTRACT
The blood-brain barrier (BBB) is a critical contributor to brain function. To understand its development and potential function in different brain regions, the postnatal (P) BBB was investigated in the mouse cortex (CTX), lateral hypothalamus, and paraventricular nucleus of the hypothalamus (PVN). Brains were examined on postnatal days (P)12, P22 and P52 for BBB competency and for pericytes as key cellular components of the BBB demarcated by immunoreactive desmin. Glucocorticoid influences (excess dexamethasone; dex) during prenatal development were also assessed for their impact on the blood vessels within these regions postnatally. At P12, there was significantly more extravascular leakage of a low molecular weight dye (fluorescein isothiocyanate) in the CTX than within hypothalamic regions. For pericytes, there were low levels of desmin immunoreactivity at P12 that increased with age for all regions. There was more desmin immunoreactivity present in the PVN at each age examined. Fetal dex exposure resulted in decreased blood vessel density within the PVN at P20. In the CTX, dex exposure increased BBB competency, in contrast to the PVN where there was a decrease in BBB competency and increased pericyte presence. Overall, unique alterations in the functioning of the BBB within the PVN may provide a novel mechanism for fetal antecedent programming that may influence adult disorders.

No MeSH data available.


Related in: MedlinePlus

Prenatal exposure to dexamethasone (dex) impacted blood–brain barrier development in the mouse cortex (CTX) and paraventricular nucleus of the hypothalamus (PVN) at P20. Example confocal images for each region are provided in panels a–f, and a quantitative summary by graph in g and h. In the CTX, there was a significant decrease in extravascular FITC leakage in dex-treated compared to vehicle-treated mice (a, d, g; p < 0.05). For the PVN, there was a significant increase in extravascular FITC leakage in offspring of dex-treated compared to vehicle-treated mice in the mid region (c, f, g; p < 0.05). There was no impact of fetal dex observed in the lateral hypothalamus (LH; b, e, g). Number of animals per group is provided in the code for the bars in panels g and h. Significant differences for treatment indicated by *p < 0.05 and **p < 0.01. Scale bar 50 µm in panel a, which applies to all images
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Fig5: Prenatal exposure to dexamethasone (dex) impacted blood–brain barrier development in the mouse cortex (CTX) and paraventricular nucleus of the hypothalamus (PVN) at P20. Example confocal images for each region are provided in panels a–f, and a quantitative summary by graph in g and h. In the CTX, there was a significant decrease in extravascular FITC leakage in dex-treated compared to vehicle-treated mice (a, d, g; p < 0.05). For the PVN, there was a significant increase in extravascular FITC leakage in offspring of dex-treated compared to vehicle-treated mice in the mid region (c, f, g; p < 0.05). There was no impact of fetal dex observed in the lateral hypothalamus (LH; b, e, g). Number of animals per group is provided in the code for the bars in panels g and h. Significant differences for treatment indicated by *p < 0.05 and **p < 0.01. Scale bar 50 µm in panel a, which applies to all images

Mentions: Given that structural blood vessel characteristics were impacted in offspring of mothers treated with dex during gestation (Fig. 4), it was important to assess the state of the BBB (Fig. 5). Importantly, the impact of fetal dex exposure on later BBB competency was opposite in the CTX versus PVN. In the CTX, there was statistically significant 12 % less extravascular FITC leakage in offspring from mothers treated with dex compared to those exposed to vehicle (Fig. 5a, d; p < 0.05). This suggests that there was an increase in the competency of the BBB due to dex-treatment in the CTX. In stark contrast, the mid region of the PVN showed a statistically significant 17 % increase in extravascular FITC leakage in dex-treated compared to vehicle-treated offspring (Fig. 5c, f, g; p < 0.05). There was a strong trend for prenatally dex-treated mice to have an increase in extravascular FITC in the rostral PVN compared to vehicle-treated (data not shown; p < 0.09) with no notable differences observed in the caudal PVN. For the LH, there was no change in extravascular FITC leakage in offspring from mothers either prenatally dex- or vehicle-treated (Fig. 5b, e). Due to the possibility of maternal injection providing a stressful stimulus that could increase endogenous glucocorticoid levels, a comparison was made between offspring of vehicle-injected mothers versus offspring from mothers who were not injected (Fig. 1). There were no differences in vascular characteristics or BBB competency when compared with non-injected mice. Together these findings suggest that fetal antecedent exposure to dex decreased the density and integrity of the blood vessels selectively within the PVN when examined in later life.Fig. 5


Development of the blood-brain barrier within the paraventricular nucleus of the hypothalamus: influence of fetal glucocorticoid excess.

Frahm KA, Tobet SA - Brain Struct Funct (2014)

Prenatal exposure to dexamethasone (dex) impacted blood–brain barrier development in the mouse cortex (CTX) and paraventricular nucleus of the hypothalamus (PVN) at P20. Example confocal images for each region are provided in panels a–f, and a quantitative summary by graph in g and h. In the CTX, there was a significant decrease in extravascular FITC leakage in dex-treated compared to vehicle-treated mice (a, d, g; p < 0.05). For the PVN, there was a significant increase in extravascular FITC leakage in offspring of dex-treated compared to vehicle-treated mice in the mid region (c, f, g; p < 0.05). There was no impact of fetal dex observed in the lateral hypothalamus (LH; b, e, g). Number of animals per group is provided in the code for the bars in panels g and h. Significant differences for treatment indicated by *p < 0.05 and **p < 0.01. Scale bar 50 µm in panel a, which applies to all images
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4481307&req=5

Fig5: Prenatal exposure to dexamethasone (dex) impacted blood–brain barrier development in the mouse cortex (CTX) and paraventricular nucleus of the hypothalamus (PVN) at P20. Example confocal images for each region are provided in panels a–f, and a quantitative summary by graph in g and h. In the CTX, there was a significant decrease in extravascular FITC leakage in dex-treated compared to vehicle-treated mice (a, d, g; p < 0.05). For the PVN, there was a significant increase in extravascular FITC leakage in offspring of dex-treated compared to vehicle-treated mice in the mid region (c, f, g; p < 0.05). There was no impact of fetal dex observed in the lateral hypothalamus (LH; b, e, g). Number of animals per group is provided in the code for the bars in panels g and h. Significant differences for treatment indicated by *p < 0.05 and **p < 0.01. Scale bar 50 µm in panel a, which applies to all images
Mentions: Given that structural blood vessel characteristics were impacted in offspring of mothers treated with dex during gestation (Fig. 4), it was important to assess the state of the BBB (Fig. 5). Importantly, the impact of fetal dex exposure on later BBB competency was opposite in the CTX versus PVN. In the CTX, there was statistically significant 12 % less extravascular FITC leakage in offspring from mothers treated with dex compared to those exposed to vehicle (Fig. 5a, d; p < 0.05). This suggests that there was an increase in the competency of the BBB due to dex-treatment in the CTX. In stark contrast, the mid region of the PVN showed a statistically significant 17 % increase in extravascular FITC leakage in dex-treated compared to vehicle-treated offspring (Fig. 5c, f, g; p < 0.05). There was a strong trend for prenatally dex-treated mice to have an increase in extravascular FITC in the rostral PVN compared to vehicle-treated (data not shown; p < 0.09) with no notable differences observed in the caudal PVN. For the LH, there was no change in extravascular FITC leakage in offspring from mothers either prenatally dex- or vehicle-treated (Fig. 5b, e). Due to the possibility of maternal injection providing a stressful stimulus that could increase endogenous glucocorticoid levels, a comparison was made between offspring of vehicle-injected mothers versus offspring from mothers who were not injected (Fig. 1). There were no differences in vascular characteristics or BBB competency when compared with non-injected mice. Together these findings suggest that fetal antecedent exposure to dex decreased the density and integrity of the blood vessels selectively within the PVN when examined in later life.Fig. 5

Bottom Line: Fetal dex exposure resulted in decreased blood vessel density within the PVN at P20.In the CTX, dex exposure increased BBB competency, in contrast to the PVN where there was a decrease in BBB competency and increased pericyte presence.Overall, unique alterations in the functioning of the BBB within the PVN may provide a novel mechanism for fetal antecedent programming that may influence adult disorders.

View Article: PubMed Central - PubMed

Affiliation: Program in Cell and Molecular Biology, Colorado State University, 1617 Campus Delivery, Fort Collins, CO, 80523-1617, USA.

ABSTRACT
The blood-brain barrier (BBB) is a critical contributor to brain function. To understand its development and potential function in different brain regions, the postnatal (P) BBB was investigated in the mouse cortex (CTX), lateral hypothalamus, and paraventricular nucleus of the hypothalamus (PVN). Brains were examined on postnatal days (P)12, P22 and P52 for BBB competency and for pericytes as key cellular components of the BBB demarcated by immunoreactive desmin. Glucocorticoid influences (excess dexamethasone; dex) during prenatal development were also assessed for their impact on the blood vessels within these regions postnatally. At P12, there was significantly more extravascular leakage of a low molecular weight dye (fluorescein isothiocyanate) in the CTX than within hypothalamic regions. For pericytes, there were low levels of desmin immunoreactivity at P12 that increased with age for all regions. There was more desmin immunoreactivity present in the PVN at each age examined. Fetal dex exposure resulted in decreased blood vessel density within the PVN at P20. In the CTX, dex exposure increased BBB competency, in contrast to the PVN where there was a decrease in BBB competency and increased pericyte presence. Overall, unique alterations in the functioning of the BBB within the PVN may provide a novel mechanism for fetal antecedent programming that may influence adult disorders.

No MeSH data available.


Related in: MedlinePlus