Ablation of astrocytic laminin impairs vascular smooth muscle cell function and leads to hemorrhagic stroke

Chen, Zu Lin; Yao, Yao; Norris, Erin H.; Kruyer, Anna; Jno-Charles, Odella; Akhmerov, Akbarshakh; Strickland, Sidney

doi:10.1083/jcb.201212032

Cited by 101 publications

(96 citation statements)

References 70 publications

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“…1b), suggesting that laminin expression is indeed abrogated in SMCs in SKO mice. Lack of laminin γ1 expression in nestin + cells has been validated before [10,19]. Here we showed that nestin + cells in NKO aorta were negative for laminin γ1 (white arrowheads, Supplemental Fig.…”

Section: Resultssupporting

confidence: 82%

“…F/F mice were crossed with SM22α-cre and nestin-cre transgenic mouse lines to generate F/F:SM22α-Cre + (SKO) and F/F:nestin-Cre + (NKO) mice, respectively. These knockout mice were born in the expected Mendelian ratios (data not shown), although NKO mice were smaller than their wild-type littermates [10]. The F/F and F/+ (heterozygous floxed laminin γ1) littermates were used as controls (Ctr).…”

Section: Resultsmentioning

confidence: 99%

“…The synthetic phenotype is usually found during development or in injured vessels, where SMCs have a round hypertrophic morphology, lose the circumferential orientation, and synthesize various extracellular matrix (ECM) proteins and other molecules at a high rate [3,5,9]. Previous work from our lab and others shows that laminin regulates contractile protein expression in SMCs [10–14]. A direct link between laminin and BP regulation, however, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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The cellular origin of laminin determines its role in blood pressure regulation

Yao

Norris

Strickland

2014

Cell. Mol. Life Sci.

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Laminin of different cellular source has distinct functions. In addition to vascular smooth muscle cells (SMCs), aorta also contains a small population of nestin+ cells, whose function remains unknown. This study investigates the role of SMC- and nestin+ cell-derived laminin in blood pressure (BP) regulation and SMC contractibility. Using mice with laminin deficiency in SMCs (SKO) or nestin+ cells (NKO), we examined laminin-dependent changes in baseline BP. Contractile protein expression was reduced in SKO but not NKO mice, consistent with their respectively low and normal baseline BP measurements. At the ultrastructural level, SKO SMCs maintained the contractile phenotype with reduced elasticity, whereas NKO SMCs switched to the synthetic phenotype and showed degeneration. Additionally, angiotensin II (Ang II) significantly increased BP in SKO but not NKO mice. It also enhanced contractile proteins to the same levels and induced SMC degeneration in both knockout mice. These data suggest that SMC laminin regulates BP via modulating contractile protein expression, whereas nestin+ cell-derived laminin contributes to SMC phenotypic switch.

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Section: Resultssupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The cellular origin of laminin determines its role in blood pressure regulation

Yao

Norris

Strickland

2014

Cell. Mol. Life Sci.

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“…In addition to endothelial cells, specific subtypes of laminin are also produced by astrocytes and pericytes (Yao et al ., 2014). Previously, it has been shown that dysregulation in production of astrocytic laminin can compromise BBB by affecting pericyte differentiation and vascular smooth muscle cell function (Chen et al ., 2013; Yao et al ., 2014). Recently, by employing a high‐resolution MRI method, blood to brain transfer of gadolinium bound to plasma proteins (shows entry of large molecules that cannot usually enter the brain) was measured regionally in a quantitative manner.…”

Section: Discussionmentioning

confidence: 99%

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

et al. 2015

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SummaryMicroglia are a proliferative population of resident brain macrophages that under physiological conditions self‐renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as ‘priming’. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first‐generation G1 mTerc−/−)‐ and late‐generation (third‐generation G3 and G4 mTerc−/−) telomerase‐deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late‐generation mTerc−/− microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc−/− microglia are comparable with microglia derived from G1 mTerc−/− mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc−/− microglia mice show an enhanced pro‐inflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age‐associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood–brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.

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“…100 In solid support of this notion, recent work revealed that genetic ablation of the laminin-g1 subunit in neurons and astrocytes disrupted astrocytic end-feet BM formation, consequently causing blood vessel disintegration and spontaneous hemorrhage in deep regions of the brain. 101 One could speculate that plasmin degradation of laminin or other components of the BM could inflict a similar effect.…”

Section: Conceptual Links Between Plasmin Activity and Blood-brain Bamentioning

confidence: 98%

Plasmin-Dependent Modulation of the Blood–Brain Barrier: A Major Consideration during tPA-Induced Thrombolysis?

Niego

Medcalf

2014

J Cereb Blood Flow Metab

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Plasmin, the principal downstream product of tissue-type plasminogen activator (tPA), is known for its potent fibrin-degrading capacity but is also recognized for many non-fibrinolytic activities. Curiously, plasmin has not been conclusively linked to blood-brain barrier (BBB) disruption during recombinant tPA (rtPA)-induced thrombolysis in ischemic stroke. This is surprising given the substantial involvement of tPA in the modulation of BBB permeability and the co-existence of tPA and plasminogen in both blood and brain throughout the ischemic event. Here, we review the work that argues a role for plasmin together with endogenous tPA or rtPA in BBB alteration, presenting the overall controversy around the topic yet creating a rational case for an involvement of plasmin in this process.

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Ablation of astrocytic laminin impairs vascular smooth muscle cell function and leads to hemorrhagic stroke

Abstract: Ablation of astrocytic laminin disrupted the interaction between vascular smooth muscle cells and astrocytes, down-regulated contractile protein expression, and weakened vascular integrity in deep brain regions, leading to hemorrhage.

Cited by 101 publications

References 70 publications

The cellular origin of laminin determines its role in blood pressure regulation

The cellular origin of laminin determines its role in blood pressure regulation

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

Plasmin-Dependent Modulation of the Blood–Brain Barrier: A Major Consideration during tPA-Induced Thrombolysis?

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