Endothelial Control of Cerebral Blood Flow

Ashby, Julianne W.; Mack, Julia J.

doi:10.1016/j.ajpath.2021.02.023

Cited by 41 publications

(30 citation statements)

References 117 publications

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“…Here, we provide evidence that DRG2 is involved in angiogenesis and vascular remodeling, in that (a) DRG2 −/− mice showed decreased blood flow in the brain. Since regulation of CBF is controlled by cerebral endothelium [ 46 ], reduction in the CBF in DRG2 −/− mice implicates the role of DRG2 in endothelium function; (b) DRG2 deficiency reduced pulmonary blood vessel density. The intensity of CD31 staining in the lung of DRG2 −/− mice was significantly reduced compared to that of wild-type mice; (c) DRG2 deficiency inhibited neovascularization of subcutaneous Matrigel implants.…”

Section: Discussionmentioning

confidence: 99%

DRG2 Depletion Promotes Endothelial Cell Senescence and Vascular Endothelial Dysfunction

Park

et al. 2022

IJMS

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Endothelial cell senescence is involved in endothelial dysfunction and vascular diseases. However, the detailed mechanisms of endothelial senescence are not fully understood. Here, we demonstrated that deficiency of developmentally regulated GTP-binding protein 2 (DRG2) induces senescence and dysfunction of endothelial cells. DRG2 knockout (KO) mice displayed reduced cerebral blood flow in the brain and lung blood vessel density. We also determined, by Matrigel plug assay, aorta ring assay, and in vitro tubule formation of primary lung endothelial cells, that deficiency in DRG2 reduced the angiogenic capability of endothelial cells. Endothelial cells from DRG2 KO mice showed a senescence phenotype with decreased cell growth and enhanced levels of p21 and phosphorylated p53, γH2AX, senescence-associated β-galactosidase (SA-β-gal) activity, and senescence-associated secretory phenotype (SASP) cytokines. DRG2 deficiency in endothelial cells upregulated arginase 2 (Arg2) and generation of reactive oxygen species. Induction of SA-β-gal activity was prevented by the antioxidant N-acetyl cysteine in endothelial cells from DRG2 KO mice. In conclusion, our results suggest that DRG2 is a key regulator of endothelial senescence, and its downregulation is probably involved in vascular dysfunction and diseases.

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Section: Discussionmentioning

confidence: 99%

DRG2 Depletion Promotes Endothelial Cell Senescence and Vascular Endothelial Dysfunction

Park

et al. 2022

IJMS

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“…It also plays a crucial role in the control of multiple important functions, acting as an endocrine organ. Among its functions is the regulation of the regional blood flow, controlling vascular tone by releasing various vasodilator molecules, such as nitric oxide (NO), prostacyclin (PGI2), or the endothelium-derived hyperpolarizing factor (EDHF), and contracting factors, such as endothelins [27,28]. It also participates in the regulation of inflammation and angiogenesis [29].…”

Section: Disruption Of Blood-brain Barrier (Bbb) In Admentioning

confidence: 99%

“…The BBB allows the selective passage of nutrients and energy to the brain, which are essential for neuronal function and preventing the entry of neurotoxic substances from the peripheral circulation. Therefore, BBB has a crucial role in the maintenance of homeostasis in the CNS by limiting transport of toxic or harmful molecules, transport of nutrients, and removal of metabolites from the brain [24,28]. Transport through the endothelial cells is mainly mediated by the expression of receptors and transporters, such as the receptor for advanced glycosylation end products (RAGE), low-density lipoprotein receptor-related protein 1 (LRP-1), and P-glycoprotein (P-gp) [37].…”

Section: Disruption Of Blood-brain Barrier (Bbb) In Admentioning

confidence: 99%

cAMP Compartmentalization in Cerebrovascular Endothelial Cells: New Therapeutic Opportunities in Alzheimer’s Disease

Viña

Seoane

Vasquez

et al. 2021

Cells

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The vascular hypothesis used to explain the pathophysiology of Alzheimer’s disease (AD) suggests that a dysfunction of the cerebral microvasculature could be the beginning of alterations that ultimately leads to neuronal damage, and an abnormal increase of the blood–brain barrier (BBB) permeability plays a prominent role in this process. It is generally accepted that, in physiological conditions, cyclic AMP (cAMP) plays a key role in maintaining BBB permeability by regulating the formation of tight junctions between endothelial cells of the brain microvasculature. It is also known that intracellular cAMP signaling is highly compartmentalized into small nanodomains and localized cAMP changes are sufficient at modifying the permeability of the endothelial barrier. This spatial and temporal distribution is maintained by the enzymes involved in cAMP synthesis and degradation, by the location of its effectors, and by the existence of anchor proteins, as well as by buffers or different cytoplasm viscosities and intracellular structures limiting its diffusion. This review compiles current knowledge on the influence of cAMP compartmentalization on the endothelial barrier and, more specifically, on the BBB, laying the foundation for a new therapeutic approach in the treatment of AD.

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“…6 Eikermann-Haerter and Huang discuss the mechanisms underlying the differences and similarities between migraine-related deep white matter hyperintensities and small blood vessel disease. 7 The review by Ashby and Mack addresses multiple modes of endothelium-derived blood flow regulation and how they may contribute to the pathophysiology of small blood vessel disease, 8 whereas Montagne et al consider the extent to which loss of pericytes and the resulting loss of endothelialpericyte crosstalk contributes to dementia pathology. 9 Access to better animal models of small blood vessel disease will tremendously enhance our understanding of mechanism and enable preclinical testing of new therapies.…”

Section: Q8mentioning

confidence: 99%

Safe and Effective Disease-Modifying Therapies for Small Blood Vessel Disease in the Brain

Arboleda‐Velásquez

2021

The American Journal of Pathology

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Disclosures: J.F.A-V is listed as an inventor in patent applications for biomarkers and treatments addressing cerebral small vessel disease.J.F.A-V is the Special Editor of the Small Blood Vessel Disease in the Brain Theme Issue.This Editorial introduces this month's special Small Blood Vessel Disease in the Brain Theme Issue, a series of reviews on small blood vessel disease in the brain addressing current knowledge, new mechanisms, biomarkers, and therapeutic approaches.

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Endothelial Control of Cerebral Blood Flow

Abstract: Small Blood Vessel Disease in the Brain Theme Issue Disclosures: None declared. This article is part of a review series on small blood vessel disease in the brain, addressing current knowledge, new mechanisms, biomarkers, and therapeutic approaches.

Cited by 41 publications

References 117 publications

DRG2 Depletion Promotes Endothelial Cell Senescence and Vascular Endothelial Dysfunction

DRG2 Depletion Promotes Endothelial Cell Senescence and Vascular Endothelial Dysfunction

cAMP Compartmentalization in Cerebrovascular Endothelial Cells: New Therapeutic Opportunities in Alzheimer’s Disease

Safe and Effective Disease-Modifying Therapies for Small Blood Vessel Disease in the Brain

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