Vascular leakage caused by loss of Akt1 is associated with impaired mural cell coverage

Introduction: Brain arteriovenous malformations (bAVMs) have an abnormal vessel wall and are prone to rupture. The mechanism of bAVM rupture is unclear. In Alk1 -deficient mice, bAVM vessels have fewer mural cells. In endoglin-deficient mice, thalidomide increases mural cells in retina AVM vessels. We hypothesize that thalidomide and its less toxic analogue, lenalidomide, improve vessel mural cell coverage and reduce microhemorrhage in Alk1 -deficient bAVM. Methods: Brain AVMs were induced in adult Alk1 2f/2f mice through induction of focal Alk1 gene deletion and angiogenic stimulation. Thalidomide was injected intraperitoneally (i.p.) twice per week for six weeks, starting either 2 weeks after model induction when bAVMs were beginning to develop or 8 weeks after when bAVMs were fully developed. Lenalidomide treatment was started 8 weeks after model induction through i.p. injection daily for six weeks. Results: Thalidomide treatment starting 2 weeks after bAVM induction reduced the number of abnormal vessels and microhemorrhage and increased vascular smooth muscle (vSM)-coverage. Thalidomide also increased the expression of platelet-derived growth factor b (pdgfb) and its receptor (pdgfr beta), indicating that pdgfg/pdgfr beta signaling is one of the mechanisms responsible for the improvement of mural cell coverage. Thalidomide and lenalidomide treatment started at the later time point also improved vSM-coverage and showed a trend toward reduction of microhemorrhage and abnormal vessel count. Conclusions: Thalidomide and lenalidomide stabilize the bAVM vessel wall and reduce microhemorrahge. Further studies are needed to determine whether these agents have a possible therapeutic value for patients.

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Dosage-dependent requirement of BMP type II receptor for maintenance of vascular integrity

Blood ◽

10.1182/blood-2006-11-058594 ◽

2007 ◽

Vol 110 (5) ◽

pp. 1502-1510 ◽

Cited By ~ 69

Author(s):

Dong Liu ◽

Jian Wang ◽

Bernd Kinzel ◽

Matthias Müeller ◽

Xiaohong Mao ◽

...

Keyword(s):

Germ Line ◽

Vascular Lesions ◽

Type Ii ◽

Cellular Mechanisms ◽

Mural Cell ◽

Vascular Integrity ◽

Akt Activation ◽

Adult Mice ◽

Cell Coverage ◽

Pulmonary Arterial

Abstract Germ-line mutations in bone morphogenic protein type II receptor (Bmpr2) confer susceptibility to pulmonary arterial hypertension (PAH), which is characterized by obstructive vascular lesions in small arteries. The molecular and cellular mechanisms that account for the etiology of this disorder remain elusive, as does the role of Bmpr2 in postnatal tissue homeostasis. Here we show that in adult mice, stably silencing Bmpr2 expression by RNA interference does not increase pulmonary arterial resistance but results in severe mucosal hemorrhage, incomplete mural cell coverage on vessel walls, and gastrointestinal hyperplasia. We present evidence that BMP receptor signaling regulates vascular remodeling during angiogenesis by maintaining the expression of endothelial guidance molecules that promote vessel patterning and maturation and by counteracting growth factor–induced AKT activation. Attenuation of this function may cause vascular dysmorphogenesis and predisposition to angioproliferative diseases. Our findings provide a mechanistic link between PAH and other diseases associated with the BMP/TGF-β pathways, such as hereditary hemorrhagic telangiectasia and juvenile polyposis syndrome.

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LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis

Blood ◽

10.1182/blood-2010-03-272443 ◽

2010 ◽

Vol 116 (23) ◽

pp. 5060-5070 ◽

Cited By ~ 78

Author(s):

Hayakazu Sumida ◽

Kyoko Noguchi ◽

Yasuyuki Kihara ◽

Manabu Abe ◽

Keisuke Yanagida ◽

...

Keyword(s):

Critical Role ◽

Lymphatic Vessels ◽

Physiological Role ◽

Lipid Mediator ◽

Mural Cell ◽

Mouse Embryogenesis ◽

Mural Cells ◽

Adult Mice ◽

Cell Coverage ◽

And Function

Abstract Lysophosphatidic acid (LPA) is a potent lipid mediator with a wide variety of biological actions mediated through G protein-coupled receptors (LPA1-6). LPA4 has been identified as a G13 protein-coupled receptor, but its physiological role is unknown. Here we show that a subset of LPA4-deficient embryos did not survive gestation and displayed hemorrhages and/or edema in many organs at multiple embryonic stages. The blood vessels of bleeding LPA4-deficient embryos were often dilated. The recruitment of mural cells, namely smooth muscle cells and pericytes, was impaired. Consistently, Matrigel plug assays showed decreased mural cell coverage of endothelial cells in the neovessels of LPA4-deficient adult mice. In situ hybridization detected Lpa4 mRNA in the endothelium of some vasculatures. Similarly, the lymphatic vessels of edematous embryos were dilated. These results suggest that LPA4 regulates establishment of the structure and function of blood and lymphatic vessels during mouse embryogenesis. Considering the critical role of autotaxin (an enzyme involved in LPA production) and Gα13 in vascular development, we suggest that LPA4 provides a link between these 2 molecules.

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Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL

Journal of Experimental Medicine ◽

10.1084/jem.20161715 ◽

2017 ◽

Vol 214 (8) ◽

pp. 2271-2282 ◽

Cited By ~ 23

Author(s):

Arturo I. Machuca-Parra ◽

Alexander A. Bigger-Allen ◽

Angie V. Sanchez ◽

Anissa Boutabla ◽

Jonathan Cardona-Vélez ◽

...

Keyword(s):

Plasma Proteins ◽

Small Vessel Disease ◽

Cell Loss ◽

Vascular Cognitive Impairment ◽

Loss Of Function ◽

Genetic Rescue ◽

Mural Cell ◽

Mural Cells ◽

Cell Coverage ◽

Necessary And Sufficient

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3. No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling.

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Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia

The Journal of Cell Biology ◽

10.1083/jcb.201603106 ◽

2016 ◽

Vol 214 (7) ◽

pp. 807-816 ◽

Cited By ~ 70

Author(s):

Nicolas Baeyens ◽

Bruno Larrivée ◽

Roxana Ola ◽

Brielle Hayward-Piatkowskyi ◽

Alexandre Dubrac ◽

...

Keyword(s):

Shear Stress ◽

Bone Morphogenetic Proteins ◽

Hereditary Hemorrhagic Telangiectasia ◽

Fluid Shear Stress ◽

Vascular System ◽

Fluid Shear ◽

Mural Cell ◽

Cell Coverage ◽

Convergence Point ◽

Dominant Disease

Morphogenesis of the vascular system is strongly modulated by mechanical forces from blood flow. Hereditary hemorrhagic telangiectasia (HHT) is an inherited autosomal-dominant disease in which arteriovenous malformations and telangiectasias accumulate with age. Most cases are linked to heterozygous mutations in Alk1 or Endoglin, receptors for bone morphogenetic proteins (BMPs) 9 and 10. Evidence suggests that a second hit results in clonal expansion of endothelial cells to form lesions with poor mural cell coverage that spontaneously rupture and bleed. We now report that fluid shear stress potentiates BMPs to activate Alk1 signaling, which correlates with enhanced association of Alk1 and endoglin. Alk1 is required for BMP9 and flow responses, whereas endoglin is only required for enhancement by flow. This pathway mediates both inhibition of endothelial proliferation and recruitment of mural cells; thus, its loss blocks flow-induced vascular stabilization. Identification of Alk1 signaling as a convergence point for flow and soluble ligands provides a molecular mechanism for development of HHT lesions.

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