scholarly journals Conserved and context-dependent roles for Pdgfrb signaling during zebrafish vascular mural cell development

2021 ◽  
Author(s):  
Koji Ando ◽  
Yu-Huan Shih ◽  
Lwaki Ebarasi ◽  
Ann Grosse ◽  
Daneal Portman ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Coronary Vessels ◽  
Structural Defects ◽  
Mural Cell ◽  
Larval Stages ◽  
Mural Cells ◽  
Brain Pericytes ◽  
Juvenile Stages ◽  
Mutant Lines

Platelet derived growth factor beta and its receptor, Pdgfrb, play essential roles in the development of vascular mural cells, including pericytes and vascular smooth muscle. To determine if this role was conserved in zebrafish, we analyzed pdgfb and pdgfrb mutant lines. Similar to mouse, pdgfb and pdgfrb mutant zebrafish lack brain pericytes and exhibit anatomically selective loss of vascular smooth muscle coverage. Despite these defects, pdgfrb mutant zebrafish did not otherwise exhibit circulatory defects at larval stages. However, beginning at juvenile stages, we observed severe cranial hemorrhage and vessel dilation associated with loss of pericytes and vascular smooth muscle cells in pdgfrb mutants. Similar to mouse, pdgfrb mutant zebrafish also displayed structural defects in the glomerulus, but normal development of hepatic stellate cells. We also noted defective mural cell investment on coronary vessels with concomitant defects in their development. Together, our studies support a conserved requirement for Pdgfrb signaling in mural cells. In addition, these mutants provide an important model for definitive investigation of mural cells during early embryonic stages without confounding secondary effects from circulatory defects.

Integrative analysis of the human brain mural cell transcriptome

2021 ◽  
pp. 0271678X2110137
Author(s):  
Benjamin D Gastfriend ◽  
Koji L Foreman ◽  
Moriah E Katt ◽  
Sean P Palecek ◽  
Eric V Shusta
Keyword(s):  
Human Brain ◽  
Cell Function ◽  
In Vitro Models ◽  
Molecular Characteristics ◽  
Mural Cell ◽  
Mural Cells ◽  
Brain Pericytes ◽  
Mouse Species ◽  
Cell Transcriptome

Brain mural cells, including pericytes and vascular smooth muscle cells, are important for vascular development, blood-brain barrier function, and neurovascular coupling, but the molecular characteristics of human brain mural cells are incompletely characterized. Single cell RNA-sequencing (scRNA-seq) is increasingly being applied to assess cellular diversity in the human brain, but the scarcity of mural cells in whole brain samples has limited their molecular profiling. Here, we leverage the combined power of multiple independent human brain scRNA-seq datasets to build a transcriptomic database of human brain mural cells. We use this combined dataset to determine human-mouse species differences in mural cell transcriptomes, culture-induced dedifferentiation of human brain pericytes, and human mural cell organotypicity, with several key findings validated by RNA fluorescence in situ hybridization. Together, this work improves knowledge regarding the molecular constituents of human brain mural cells, serves as a resource for hypothesis generation in understanding brain mural cell function, and will facilitate comparative evaluation of animal and in vitro models.

scholarly journals Mural Cell-Specific Deletion of Cerebral Cavernous Malformation 3 in the Brain Induces Cerebral Cavernous Malformations

2020 ◽  
Vol 40 (9) ◽  
pp. 2171-2186
Author(s):  
Kang Wang ◽  
Haifeng Zhang ◽  
Yun He ◽  
Quan Jiang ◽  
Yoshiaki Tanaka ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Adhesion Formation ◽  
Single Layer ◽  
Cerebral Cavernous Malformations ◽  
Mural Cell ◽  
Cavernous Malformations ◽  
Mural Cells ◽  
Brain Pericytes ◽  
The Brain ◽  
Specific Deletion

Objective: Cerebral cavernous malformations (CCM), consisting of dilated capillary channels formed by a single layer of endothelial cells lacking surrounding mural cells. It is unclear why CCM lesions are primarily confined to brain vasculature, although the 3 CCM-associated genes ( CCM1 , CCM2 , and CCM3 ) are ubiquitously expressed in all tissues. We aimed to determine the role of CCM gene in brain mural cell in CCM pathogenesis. Approach and Results: SM22α -Cre was used to drive a specific deletion of Ccm3 in mural cells, including pericytes and smooth muscle cells (Ccm3smKO). Ccm3smKO mice developed CCM lesions in the brain with onset at neonatal stages. One-third of Ccm3smKO mice survived upto 6 weeks of age, exhibiting seizures, and severe brain hemorrhage. The early CCM lesions in Ccm3smKO neonates were loosely wrapped by mural cells, and adult Ccm3smKO mice had clustered and enlarged capillary channels (caverns) formed by a single layer of endothelium lacking mural cell coverage. Importantly, CCM lesions throughout the entire brain in Ccm3smKO mice, which more accurately mimicked human disease than the current endothelial cell-specific CCM3 deletion models. Mechanistically, CCM3 loss in brain pericytes dramatically increased paxillin stability and focal adhesion formation, enhancing ITG-β1 (integrin β1) activity and extracellular matrix adhesion but reducing cell migration and endothelial cell-pericyte associations. Moreover, CCM3-wild type, but not a paxillin-binding defective mutant, rescued the phenotypes in CCM3-deficient pericytes. Conclusions: Our data demonstrate for the first time that deletion of a CCM gene in the brain mural cell induces CCM pathogenesis.

scholarly journals Morphogenesis and differentiation of embryonic vascular smooth muscle cells in zebrafish

2018 ◽  
Author(s):  
Thomas R. Whitesell ◽  
Paul Chrystal ◽  
Jae-Ryeon Ryu ◽  
Nicole Munsie ◽  
Ann Grosse ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Critical Role ◽  
Muscle Cells ◽  
Mural Cells

AbstractDespite the critical role of vascular mural cells (smooth muscle cells and pericytes) in supporting the endothelium of blood vessels, we know little of their early morphogenesis and differentiation. foxc1b:EGFP expressing cells in zebrafish associate with the vascular endothelium (kdrl) and co-express a smooth muscle marker (acta2), but not a pericyte marker (pdgfrβ). The expression of foxc1b in early peri-endothelial mesenchymal cells allows us to follow the morphogenesis of mesenchyme into acta2 expressing vascular smooth muscle cells. We show that mural cells expressing different markers associate with vessels of different diameters, depending on their embryonic location and developmental timing, suggesting marker expression is predictive of functional differences. We identify gene expression signatures for an enriched vascular smooth muscle cell population (foxc1b + acta2) and all smooth muscle (acta2) using fluorescence-activated cell sorting and RNA-Seq. Finally, we demonstrate that progressive loss of foxc1a/foxc1b results in decreased smooth muscle cell coverage. Together, our data highlight the early cellular dynamics and transcriptome profiles of smooth muscle cells in vivo, using foxc1b as a unique tool to probe vascular smooth muscle cell differentiation.Summary StatementTracing the morphogenesis and transcriptome of early vascular smooth muscle cells using foxc1b

scholarly journals Organizational Hierarchy and Structural Diversity of Microvascular Pericytes in Adult Mouse Cortex

2017 ◽  
Author(s):  
Roger I. Grant ◽  
David A. Hartmann ◽  
Robert G. Underly ◽  
Andrée-Anne Berthiaume ◽  
Narayan R. Bhat ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Actin ◽  
Muscle Cells ◽  
Cell Types ◽  
Mural Cell ◽  
Mural Cells ◽  
Mouse Cortex ◽  
Transitional Cells ◽  
Brain Microvasculature

ABSTRACTSmooth muscle cells and pericytes, together called mural cells, coordinate many distinct vascular functions. Smooth muscle cells are ring-shaped and cover arterioles with circumferential processes, whereas pericytes extend thin processes that run longitudinally along capillaries. In between these canonical mural cell types are cells with mixed phenotype of both smooth muscle cells and pericytes. Recent studies suggest that these transitional cells are critical for controlling blood flow to the capillary bed during health and disease, but there remains confusion on how to identify them and where they are located in the brain microvasculature. To address this issue, we measured the morphology, vascular territory, and α-smooth muscle actin content of structurally diverse mural cells in adult mouse cortex. We first imaged intact 3-D vascular networks to establish the locations of major gradations in mural cell appearance as arterioles branched into capillaries. We then imaged individual mural cells occupying the regions within these gradations. This revealed two transitional cells that were often similar in appearance, but with sharply contrasting levels of α-smooth muscle actin. Our findings highlight the diversity of mural cell morphologies in brain microvasculature, and provide guidance for identification and categorization of mural cell types.

Coronary vascular smooth muscle function in E. coli endotoxemia in dogs

1991 ◽  
Vol 260 (3) ◽  
pp. H832-H841 ◽  
Author(s):  
J. L. Parker ◽  
R. S. Keller ◽  
D. V. DeFily ◽  
M. H. Laughlin ◽  
M. J. Novotny ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Coronary Arteries ◽  
Coronary Vessels ◽  
Left Ventricular ◽  
Saline Control ◽  
Apparent Lack ◽  
Relaxation Responses

The purpose of this study was to determine whether intrinsic contraction-relaxation properties of coronary arteries are altered during acute gram-negative endotoxemia. Coronary vascular smooth muscle (VSM) was evaluated in vitro using large and small left circumflex coronary ring preparations isolated from dogs 4 h after administration of either saline (control; C) or 1.5 mg/kg Escherichia coli endotoxin (ET). ET dogs exhibited marked systemic hypotension and cardiovascular depression throughout the 4-h in vivo phase of the study accompanied by reduction in total left ventricular myocardial blood flow. Isolated coronary vessels were stretched to the apex of the length-contractile tension curve; no differences were observed in length-active or length-passive tension (vessel compliance) relationships between C and ET vessels. Isometric contractions produced by K+ and prostaglandin F2 alpha (PGF2 alpha) were similar in C and ET coronary arteries. VSM relaxant responses to nitroprusside (NP; 10(-10) to 10(-4) M) were also similar in C and ET vessels. In contrast to the apparent lack of effect of ET on directly acting VSM agents, relaxation responses to the endothelial-dependent vasodilator acetylcholine (ACh) were significantly less in ET vessels. Impaired vasodilator response to ACh was not improved by in vivo treatment with the combination antioxidant therapy of allopurinol, superoxide dismutase, and catalase. We conclude that both depolarization (K+) and receptor (PGF2 alpha)-mediated contractile mechanisms, as well as basal cGMP (NP)-mediated vasodilator mechanisms, remained functional in coronary vasculature during acute endotoxemia. Inhibition of ACh-mediated relaxation in ET vessels suggests altered endothelial-dependent vasodilation in coronary arteries during endotoxemia, but this change did not seem to be associated causally with oxygen free radicals.

The Neurovascular Unit: Focus on the Regulation of Arterial Smooth Muscle Cells

2020 ◽  
Vol 16 (5) ◽  
pp. 502-515 ◽  
Author(s):  
Patrícia Quelhas ◽  
Graça Baltazar ◽  
Elisa Cairrao
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Blood Vessels ◽  
Neurovascular Unit ◽  
Muscle Cells ◽  
Cerebral Blood Vessels ◽  
Mural Cells ◽  
Brain Pericytes ◽  
The Brain

The neurovascular unit is a physiological unit present in the brain, which is constituted by elements of the nervous system (neurons and astrocytes) and the vascular system (endothelial and mural cells). This unit is responsible for the homeostasis and regulation of cerebral blood flow. There are two major types of mural cells in the brain, pericytes and smooth muscle cells. At the arterial level, smooth muscle cells are the main components that wrap around the outside of cerebral blood vessels and the major contributors to basal tone maintenance, blood pressure and blood flow distribution. They present several mechanisms by which they regulate both vasodilation and vasoconstriction of cerebral blood vessels and their regulation becomes even more important in situations of injury or pathology. In this review, we discuss the main regulatory mechanisms of brain smooth muscle cells and their contributions to the correct brain homeostasis.

scholarly journals Hepatocyte growth factor mediates angiopoietin-induced smooth muscle cell recruitment

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1260-1266 ◽  
Author(s):  
Hanako Kobayashi ◽  
Laura M. DeBusk ◽  
Yael O. Babichev ◽  
Daniel J. Dumont ◽  
Pengnian Charles Lin
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Mural Cell ◽  
Mural Cells ◽  
Hepatocyte Growth ◽  
Vascular Maturation

Abstract Communication between endothelial cells (ECs) and mural cells is critical in vascular maturation. Genetic studies suggest that angiopoietin/Tie2 signaling may play a role in the recruitment of pericytes or smooth muscle cells (SMCs) during vascular maturation. However, the molecular mechanism is unclear. We used microarray technology to analyze genes regulated by angiopoietin-1 (Ang1), an agonist ligand for Tie2, in endothelial cells (ECs). We observed that hepatocyte growth factor (HGF), a mediator of mural cell motility, was up-regulated by Ang1 stimulation. We confirmed this finding by Northern blot and Western blot analyses in cultured vascular endothelial cells. Furthermore, stimulation of ECs with Ang1 increased SMC migration toward endothelial cells in a coculture assay. Addition of a neutralizing anti-HGF antibody inhibited Ang1-induced SMC recruitment, indicating that the induction of SMC migration by Ang1 was caused by the increase of HGF. Interestingly, Ang2, an antagonist ligand of Tie2, inhibited Ang1-induced HGF production and Ang1-induced SMC migration. Finally, we showed that deletion of Tie2 in transgenic mouse reduced HGF production. Collectively, our data reveal a novel mechanism of Ang/Tie2 signaling in regulating vascular maturation and suggest that a delicate balance between Ang1 and Ang2 is critical in this process.

scholarly journals Mural Cells: Potential Therapeutic Targets to Bridge Cardiovascular Disease and Neurodegeneration

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 593
Author(s):  
Alexander Lin ◽  
Niridu Jude Peiris ◽  
Harkirat Dhaliwal ◽  
Maria Hakim ◽  
Weizhen Li ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Neurodegenerative Diseases ◽  
Structural Integrity ◽  
Vascular System ◽  
Vascular Wall ◽  
Cell Plasticity ◽  
Mural Cell ◽  
Mural Cells ◽  
Heterogenous Population

Mural cells collectively refer to the smooth muscle cells and pericytes of the vasculature. This heterogenous population of cells play a crucial role in the regulation of blood pressure, distribution, and the structural integrity of the vascular wall. As such, dysfunction of mural cells can lead to the pathogenesis and progression of a number of diseases pertaining to the vascular system. Cardiovascular diseases, particularly atherosclerosis, are perhaps the most well-described mural cell-centric case. For instance, atherosclerotic plaques are most often described as being composed of a proliferative smooth muscle cap accompanied by a necrotic core. More recently, the role of dysfunctional mural cells in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, is being recognized. In this review, we begin with an exploration of the mechanisms underlying atherosclerosis and neurodegenerative diseases, such as mural cell plasticity. Next, we highlight a selection of signaling pathways (PDGF, Notch and inflammatory signaling) that are conserved across both diseases. We propose that conserved mural cell signaling mechanisms can be exploited for the identification or development of dual-pronged therapeutics that impart both cardio- and neuroprotective qualities.

scholarly journals Heterogeneous pdgfrβ+ cells regulate coronary vessel development and revascularization during heart regeneration

2021 ◽  
Author(s):  
Subir Kapuria ◽  
Haipeng Bai ◽  
Juancarlos Fierros ◽  
Ying Huang ◽  
Feiyang Ma ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Coronary Arteries ◽  
Heart Development ◽  
Coronary Vessel ◽  
Heart Regeneration ◽  
Atrioventricular Canal ◽  
Mural Cell ◽  
Mural Cells ◽  
Vessel Development ◽  
Zebrafish Heart

ABSTRACTEndothelial cells emerge from the atrioventricular canal (AVC) to form nascent coronary blood vessels in the juvenile zebrafish heart. We found that pdgfrβ is first expressed in the epicardium around the AVC and later becomes localized mainly in the mural cells. pdgfrβ mutant fish display severe defects in mural cell recruitment and coronary vessel development. pdgfrβ+ mural cells are heterogeneous and those associated with coronary arteries also express cxcl12b. Mural cells positive for both pdgfrβ and cxcl12b transgenic reporters had elevated expression of smooth muscle cell genes. Interestingly, these mural cells were associated with coronary arteries even in the absence of Pdgfrβ, although smooth muscle gene expression was downregulated in these cells. We found that pdgfrβ expression dynamically changes in the epicardium derived cells, which we found to be a heterogeneous population. mdka was identified as a gene upregulated in subpopulations of pdgfrβ+ cells during heart regeneration. However, pdgfrβ but not mdka mutants showed defects in heart regeneration. Our results demonstrated that pdgfrβ+ cells and Pdgfrβ signaling are essential for coronary development and heart regeneration.SUMMARY STATEMENTHeterogeneous pdgfrβ positive cells are present in developing and regenerating zebrafish hearts and are required for development of mural cells and their association with the nascent coronary vessels during zebrafish heart development and regeneration.

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