Pericyte–endothelial cell interaction increases MMP-9 secretion at the blood–brain barrier in vitro

Zozulya, Alla L.; Weidenfeller, Christian; Galla, Hans‐Joachim

doi:10.1016/j.brainres.2007.10.099

Cited by 98 publications

(72 citation statements)

References 48 publications

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“…We postulate that leakage at pericyte somata is an intermediate step between these classic forms of BBB disruption. The concentrated activation of MMP-9 at the pericyte somata likely leads to degradation of the underlying tight junction complexes (Yang et al, 2007), while the intervening regions of the capillary bed maintain tight junction integrity but exhibit increased endothelial caveolae (Krueger et al, 2013;Nahirney et al, 2016). If so, there may be conditions under which both transcellular and paracellular leakage routes coexist along the same capillary segments.…”

Section: Discussionmentioning

confidence: 99%

“…More recent work has suggested that capillary pericytes die earlier than other cells of the neurovascular unit during stroke (Hall et al, 2014). The most well studied aspect of this vulnerability is the effect of the aberrant contraction of pericytes (or closely related smooth muscle cells), which can influence capillary diameter and the quality of cerebral blood flow during reperfusion (Peppiatt et al, 2006;Yemisci et al, 2009;Fernández-Klett et al, 2010;Hall et al, 2014;Hill et al, 2015;Attwell et al, 2016). However, another consequence of early pericyte death could be BBB disruption, which is relatively unexplored.…”

Section: Introductionmentioning

confidence: 99%

“…Increased BBB permeability worsens stroke outcome by exposing neurons to blood components, increasing tissue edema (Larrue et al, 1997) and limiting the window for thrombolytic treatment (Hawkins and Davis, 2005;Desilles et al, 2013). Cerebral pericytes may play a role in BBB changes after stroke, as they are essential for the proper formation and maintenance of the BBB in the normal brain (Winkler et al, 2011;Liu et al, 2012). Their continuous signaling with the endothelium promotes normal tight junction development, and regulates vesicular trafficking and immune cell infiltration across the endothelium (Armulik et al, 2005;Daneman et al, 2010;Ben-Zvi et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…However, another consequence of early pericyte death could be BBB disruption, which is relatively unexplored. Cultured pericytes have recently been shown to produce matrix metalloproteinases (MMPs;Thanabalasundaram et al, 2011;Takahashi et al, 2014), which are key mediators of BBB disruption during stroke (Yang et al, 2007;Barr et al, 2010) and during small-vessel disease in dementia (Weekman and Wilcock, 2015). In particular, various inflammatory signaling cascades can induce pericyte MMP-9 expression in vitro (Takata et al, 2011;Machida et al, 2015) and in vivo (Gurney et al, 2006;Bell et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Pericytes as Inducers of Rapid, Matrix Metalloproteinase-9-Dependent Capillary Damage during Ischemia

Underly¹,

Levy²,

Hartmann³

et al. 2017

J. Neurosci.

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Blood-brain barrier disruption (BBB) and release of toxic blood molecules into the brain contributes to neuronal injury during stroke and other cerebrovascular diseases. While pericytes are builders and custodians of the BBB in the normal brain, their impact on BBB integrity during ischemia remains unclear. We imaged pericyte-labeled transgenic mice with in vivo two-photon microscopy to examine the relationship between pericytes and blood plasma leakage during photothrombotic occlusion of cortical capillaries. Upon cessation of capillary flow, we observed that plasma leakage occurred with three times greater frequency in regions where pericyte somata adjoined the endothelium. Pericyte somata covered only 7% of the total capillary length in cortex, indicating that a disproportionate amount of leakage occurred from a small fraction of the capillary bed. Plasma leakage was preceded by rapid activation of matrix metalloproteinase (MMP) at pericyte somata, which was visualized at high resolution in vivo using a fluorescent probe for matrix metalloproteinase-2/9 activity, fluorescein isothiocyanate (FITC)-gelatin. Coinjection of an MMP-9 inhibitor, but not an MMP-2 inhibitor, reduced pericyteassociated FITC-gelatin fluorescence and plasma leakage. These results suggest that pericytes contribute to rapid and localized proteolytic degradation of the BBB during cerebral ischemia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pericytes as Inducers of Rapid, Matrix Metalloproteinase-9-Dependent Capillary Damage during Ischemia

Underly¹,

Levy²,

Hartmann³

et al. 2017

J. Neurosci.

View full text Add to dashboard Cite

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“…In addition, PCs were shown to protect barrier properties under conditions of oxygen deprivation (Al Ahmad et al, 2009). On the other hand, Zozulya and collegues could recently demonstrate that PC conditioned medium or co-culture of PCs with porcine brain ECs increase the expression of the matrix metallo-protease 9 (MMP-9) in ECs, a marker for angiogenic vessel (Zozulya et al, 2008). Consequently, the transendothelial electrical resistance (TEER) of ECs was reduced by the PC co-culture, indicating reduced barrier properties in these cells.…”

Section: Molecular Mechanisms Of Blood-brain Barrier Induction and DImentioning

confidence: 99%

Current concepts of blood-brain barrier development

Liebner¹,

Czupalla²,

Wolburg³

2011

Int. J. Dev. Biol.

188

149

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Homeostasis of the central nervous system (CNS) microenvironment is essential for its normal function and is maintained by the blood-brain barrier (BBB). The BBB proper is made up of endothelial cells (ECs) interconnected by tight junctions (TJs) that reveal a unique morphology and biochemical composition of the body's vasculature. In this article, we focus on developmental aspects of the BBB and describe morphological as well as molecular special features of the neurovascular unit (NVU) involved in barrier induction. Recently, we and others identified the Wnt/bcatenin pathway as crucial for brain angiogenesis, TJ and BBB formation. Based on these findings we discuss other pathways and molecular interactions for BBB establishment and maintenance. At the morphological level, our concept favors a major role for polarized astrocytes (ACs) therein. Orthogonal arrays of particles (OAPs) that are the morphological correlate of the water channel protein aquaporin-4 (AQP4) are specifically formed in the membrane of the AC endfoot. The polarized AC endfoot and hence OAPs are dependent on agrin and dystroglycan, of which agrin is a developmentally regulated extracellular matrix (ECM) component. Understanding the mechanisms leading to BBB development will be key to the understanding of barrier maintenance that is crucial for, but frequently disturbed, in the diseased adult brain.

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