The Diaphragms of Fenestrated Endothelia: Gatekeepers of Vascular Permeability and Blood Composition

As a key component of the vertebrate neuroendocrine system, the pituitary gland relies on the progressive and coordinated development of distinct hormone-producing cell types and an invading vascular network. The molecular mechanisms that drive formation of the pituitary vasculature, which is necessary for regulated synthesis and secretion of hormones that maintain homeostasis, metabolism, and endocrine function, remain poorly understood. Here, we report that expression of integrin β1 in embryonic pituitary epithelial cells is required for angiogenesis in the developing mouse pituitary gland. Deletion of pituitary epithelial integrin β1 before the onset of angiogenesis resulted in failure of invading endothelial cells to recruit pericytes efficiently, whereas deletion later in embryogenesis led to decreased vascular density and lumen formation. In both cases, lack of epithelial integrin β1 was associated with a complete absence of vasculature in the pituitary gland at birth. Within pituitary epithelial cells, integrin β1 directs a large transcriptional program that includes components of the extracellular matrix and associated signaling factors that are linked to the observed non-cell-autonomous effects on angiogenesis. We conclude that epithelial integrin β1 functions as a critical and canonical regulator of developmental angiogenesis in the pituitary gland, thus providing insight into the long-standing systems biology conundrum of how vascular invasion is coordinated with tissue development.angiogenesis | integrin β1 | pituitary gland | mice

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“…2A). This result was verified with a second, independent endothelial cell marker, PLVAP (plasmalemmal vesicle-associated protein) (19) (Fig. 2B).…”

Section: Resultssupporting

confidence: 63%

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland

Scully

Skowronska‐Krawczyk

Krawczyk

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Although it was previously reported that fenestrae density may contribute to the acute regulation of molecule entry into tissues due to their rapid turnover/appearance (3), no change in mean fenestrae diameter or density was detected. We cannot, however, exclude a role for alterations in the composition of fenestrae diaphragms, which act as size-selective molecular sieves involved in the regulation of basal permeability (42,43).…”

Section: Islet Blood Flow In Vivo Is Unchanged By Acute Increases In mentioning

confidence: 94%

Metabolism Regulates Exposure of Pancreatic Islets to Circulating Molecules In Vivo

et al. 2015

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Pancreatic b-cells modulate insulin secretion through rapid sensing of blood glucose and integration of gutderived signals. Increased insulin demand during pregnancy and obesity alters islet function and mass and leads to gestational diabetes mellitus and type 2 diabetes in predisposed individuals. However, it is unclear how blood-borne factors dynamically access the islets of Langerhans. Thus, understanding the changes in circulating molecule distribution that accompany compensatory b-cell expansion may be key to developing novel antidiabetic therapies. Here, using two-photon microscopy in vivo in mice, we demonstrate that islets are almost instantly exposed to peaks of circulating molecules, which rapidly pervade the tissue before clearance. In addition, both gestation and short-term high-fat-diet feeding decrease molecule extravasation and uptake rates in vivo in islets, independently of b-cell expansion or islet blood flow velocity. Together, these data support a role for islet vascular permeability in shaping b-cell adaptive responses to metabolic demand by modulating the access and sensing of circulating molecules.

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“…1c) allow a facilitated diffusion into the stroma of molecules with molecular weight up to ~ 800 kDa (reviewed in [149]). The formation and maintenance of the fenestrations and their diaphragms involve the plasmalemma vesicle associated protein (Plvap) gene [143] and are under the control of the choroidal epithelium via a basolateral secretion of vascular endothelial growth factor (VEGF). Neutralizing choroidal VEGF production leads to strong morphological and functional alterations of the choroidal vasculature, with presumable consequences on CSF secretion and composition [86].…”

Section: Choroid Plexus Morphology In Relation To Blood-csf Exchangesmentioning

confidence: 99%

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

et al. 2018

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The barrier between the blood and the ventricular cerebrospinal fluid (CSF) is located at the choroid plexuses. At the interface between two circulating fluids, these richly vascularized veil-like structures display a peculiar morphology explained by their developmental origin, and fulfill several functions essential for CNS homeostasis. They form a neuroprotective barrier preventing the accumulation of noxious compounds into the CSF and brain, and secrete CSF, which participates in the maintenance of a stable CNS internal environment. The CSF circulation plays an important role in volume transmission within the developing and adult brain, and CSF compartments are key to the immune surveillance of the CNS. In these contexts, the choroid plexuses are an important source of biologically active molecules involved in brain development, stem cell proliferation and differentiation, and brain repair. By sensing both physiological changes in brain homeostasis and peripheral or central insults such as inflammation, they also act as sentinels for the CNS. Finally, their role in the control of immune cell traffic between the blood and the CSF confers on the choroid plexuses a function in neuroimmune regulation and implicates them in neuroinflammation. The choroid plexuses, therefore, deserve more attention while investigating the pathophysiology of CNS diseases and related comorbidities.

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The Diaphragms of Fenestrated Endothelia: Gatekeepers of Vascular Permeability and Blood Composition

Cited by 196 publications

References 52 publications

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland

Epithelial cell integrin β1 is required for developmental angiogenesis in the pituitary gland

Metabolism Regulates Exposure of Pancreatic Islets to Circulating Molecules In Vivo

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

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