scholarly journals BMP-SMAD1/5 Signaling Regulates Retinal Vascular Development

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 488 ◽  
Author(s):  
Andreas Benn ◽  
Florian Alonso ◽  
Jo Mangelschots ◽  
Elisabeth Génot ◽  
Marleen Lox ◽  
...  
Keyword(s):  
Vascular Development ◽  
Bmp Signaling ◽  
Loop Formation ◽  
Vessel Formation ◽  
Sprouting Angiogenesis ◽  
Intussusceptive Angiogenesis ◽  
Morphogenetic Protein ◽  
Vessel Regression ◽  
Early Mouse ◽  
Tip Cells

Vascular development is an orchestrated process of vessel formation from pre-existing vessels via sprouting and intussusceptive angiogenesis as well as vascular remodeling to generate the mature vasculature. Bone morphogenetic protein (BMP) signaling via intracellular SMAD1 and SMAD5 effectors regulates sprouting angiogenesis in the early mouse embryo, but its role in other processes of vascular development and in other vascular beds remains incompletely understood. Here, we investigate the function of SMAD1/5 during early postnatal retinal vascular development using inducible, endothelium-specific deletion of Smad1 and Smad5. We observe the formation of arterial-venous malformations in areas with high blood flow, and fewer and less functional tip cells at the angiogenic front. The vascular plexus region is remarkably hyperdense and this is associated with reduced vessel regression and aberrant vascular loop formation. Taken together, our results highlight important functions of SMAD1/5 during vessel formation and remodeling in the early postnatal retina.

scholarly journals Ultrastructural Study of Platelet Behavior and Interrelationship in Sprouting and Intussusceptive Angiogenesis during Arterial Intimal Thickening Formation

2021 ◽  
Vol 22 (23) ◽  
pp. 13001
Author(s):  
Lucio Díaz-Flores ◽  
Ricardo Gutiérrez ◽  
Maria Pino García ◽  
Miriam González-Gómez ◽  
Lucio Díaz-Flores ◽  
...  
Keyword(s):  
Ultrastructural Study ◽  
Vascular Diseases ◽  
Ultrastructural Observation ◽  
Intimal Thickening ◽  
Sprouting Angiogenesis ◽  
Intussusceptive Angiogenesis ◽  
Arterial Lumen ◽  
Vessel Regression ◽  
Aggregation Of Platelets ◽  
Bypass Stenosis

Platelets in atherosclerosis, bypass stenosis, and restenosis have been extensively assessed. However, a sequential ultrastructural study of platelets in angiogenesis during the early phases of these lesions has received less attention. Our objective was the study of platelets in angiogenesis and vessel regression during intimal thickening (IT) formation, a precursor process of these occlusive vascular diseases. For this purpose, we used an experimental model of rat occluded arteries and procedures for ultrastructural observation. The results show (a) the absence of platelet adhesion in the de-endothelialized occluded arterial segment isolated from the circulation, (b) that intraarterial myriad platelets contributed from neovessels originated by sprouting angiogenesis from the periarterial microvasculature, (c) the association of platelets with blood components (fibrin, neutrophils, macrophages, and eosinophils) and non-polarized endothelial cells (ECs) forming aggregates (spheroids) in the arterial lumen, (d) the establishment of peg-and-socket junctions between platelets and polarized Ecs during intussusceptive angiogenesis originated from the EC aggregates, with the initial formation of IT, and (e) the aggregation of platelets in regressing neovessels (‘transitory paracrine organoid’) and IT increases. In conclusion, in sprouting and intussusceptive angiogenesis and vessel regression during IT formation, we contribute sequential ultrastructural findings on platelet behavior and relationships, which can be the basis for further studies using other procedures.

scholarly journals Intussusceptive Angiogenesis and Peg–Socket Junctions between Endothelial Cells and Smooth Muscle Cells in Early Arterial Intimal Thickening

2020 ◽  
Vol 21 (21) ◽  
pp. 8049
Author(s):  
Lucio Díaz-Flores ◽  
Ricardo Gutiérrez ◽  
Mª Pino García ◽  
Sara Gayoso ◽  
José Luís Carrasco ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Intimal Thickening ◽  
Sprouting Angiogenesis ◽  
Intussusceptive Angiogenesis ◽  
Vessel Regression ◽  
Ultrathin Sections ◽  
Immunohistochemical Techniques

Angiogenesis in arterial intimal thickening (AIT) has been considered mainly in late AIT stages and only refers to sprouting angiogenesis. We assess angiogenesis during early AIT development and the occurrence of the intussusceptive type. For this purpose, we studied AIT development in (a) human arteries with vasculitis in gallbladders with acute cholecystitis and urgent (n = 25) or delayed (n = 20) cholecystectomy, using immunohistochemical techniques and (b) experimentally occluded arterial segments (n = 56), using semithin and ultrathin sections and electron microscopy. The results showed transitory angiogenic phenomena, with formation of an important microvasculature, followed by vessel regression. In addition to the sequential description of angiogenic and regressive findings, we mainly contribute (a) formation of intravascular pillars (hallmarks of intussusception) during angiogenesis and vessel regression and (b) morphological interrelation between endothelial cells (ECs) in the arterial wall and vascular smooth muscle cells (VSMCs), which adopt a pericytic arrangement and establish peg-and-socket junctions with ECs. In conclusion, angiogenesis and vessel regression play an important role in AIT development in the conditions studied, with participation of intussusceptive angiogenesis during the formation and regression of a provisional microvasculature and with morphologic interrelation between ECs and VSMCs.

scholarly journals Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling

2021 ◽  
Vol 7 (7) ◽  
pp. eabf1798
Author(s):  
A. Murashima-Suginami ◽  
H. Kiso ◽  
Y. Tokita ◽  
E. Mihara ◽  
Y. Nambu ◽  
...  
Keyword(s):  
Tooth Development ◽  
Bmp Signaling ◽  
Tooth Agenesis ◽  
Tooth Regeneration ◽  
Missing Teeth ◽  
Morphogenetic Protein ◽  
Genetic Abnormalities ◽  
Direct Binding ◽  
Tooth Germs ◽  
Lipoprotein Receptor Related Protein

Uterine sensitization–associated gene-1 (USAG-1) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor–related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through USAG-1 knockout or anti–USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that USAG-1 controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti–USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

scholarly journals Emerging Role of AP-1 Transcription Factor JunB in Angiogenesis and Vascular Development

2021 ◽  
Vol 22 (6) ◽  
pp. 2804
Author(s):  
Yasuo Yoshitomi ◽  
Takayuki Ikeda ◽  
Hidehito Saito-Takatsuji ◽  
Hideto Yonekura
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Blood Vessel ◽  
Vascular Endothelial Cells ◽  
Vascular Development ◽  
Endothelial Cell Migration ◽  
Vascular Endothelial ◽  
Blood Vessel Formation ◽  
Vessel Formation

Blood vessels are essential for the formation and maintenance of almost all functional tissues. They play fundamental roles in the supply of oxygen and nutrition, as well as development and morphogenesis. Vascular endothelial cells are the main factor in blood vessel formation. Recently, research findings showed heterogeneity in vascular endothelial cells in different tissue/organs. Endothelial cells alter their gene expressions depending on their cell fate or angiogenic states of vascular development in normal and pathological processes. Studies on gene regulation in endothelial cells demonstrated that the activator protein 1 (AP-1) transcription factors are implicated in angiogenesis and vascular development. In particular, it has been revealed that JunB (a member of the AP-1 transcription factor family) is transiently induced in endothelial cells at the angiogenic frontier and controls them on tip cells specification during vascular development. Moreover, JunB plays a role in tissue-specific vascular maturation processes during neurovascular interaction in mouse embryonic skin and retina vasculatures. Thus, JunB appears to be a new angiogenic factor that induces endothelial cell migration and sprouting particularly in neurovascular interaction during vascular development. In this review, we discuss the recently identified role of JunB in endothelial cells and blood vessel formation.

scholarly journals GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone

2020 ◽  
Vol 117 (9) ◽  
pp. 4910-4920 ◽  
Author(s):  
Joonho Suh ◽  
Na-Kyung Kim ◽  
Seung-Hoon Lee ◽  
Je-Hyun Eom ◽  
Youngkyun Lee ◽  
...  
Keyword(s):  
Bone Mass ◽  
Muscle Mass ◽  
Transforming Growth Factor ◽  
Bone Fractures ◽  
Muscle Growth ◽  
Transforming Growth Factor Β ◽  
Biochemical Properties ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Perinatal Lethality

Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor β (TGF-β) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality ofGdf11null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show thatGdf11null mice, despite significantly down-regulatingMstnexpression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed inMstnnull mice that display enhanced bone mass. Mechanistically,Mstndeletion up-regulatesGdf11expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlikeMstnnull mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.

scholarly journals Resistance Mechanisms of Anti-angiogenic Therapy and Exosomes-Mediated Revascularization in Cancer

2020 ◽  
Vol 8 ◽  
Author(s):  
Ye Zeng ◽  
Bingmei M. Fu
Keyword(s):  
Vasculogenic Mimicry ◽  
Resistance Mechanisms ◽  
Vascular Endothelial ◽  
Beneficial Effects ◽  
Sprouting Angiogenesis ◽  
Intussusceptive Angiogenesis ◽  
Angiogenic Therapy ◽  
Tumor Neovascularization ◽  
Endothelial Growth Factor

Anti-angiogenic therapies (AATs) have been widely used for cancer treatment. But the beneficial effects of AATs are short, because AAT-induced tumor revascularization facilitates the tumor relapse. In this mini-review, we described different forms of tumor neovascularization and revascularization including sprouting angiogenesis, vessel co-option, intussusceptive angiogenesis, and vasculogenic mimicry, all of which are closely mediated by vascular endothelial growth factor (VEGF), angiopoietins, matrix metalloproteinases, and exosomes. We also summarized the current findings for the resistance mechanisms of AATs including enhancement in pro-angiogenic cytokines, heterogeneity in tumor-associated endothelial cells (ECs), crosstalk between tumor cells and ECs, masking of extracellular vesicles, matrix stiffness and contributions from fibroblasts, macrophages and adipocytes in the tumor microenvironment. We highlighted the revascularization following AATs, particularly the role of exosome stimulating factors such as hypoxia and miRNA, and that of exosomal cargos such as cytokines, miRNAs, lncRNAs, and circRNAs from the tumor ECs in angiogenesis and revascularization. Finally, we proposed that renormalization of tumor ECs would be a more efficient cancer therapy than the current AATs.

Extracellular regulation of BMP signaling: welcome to the matrix

2017 ◽  
Vol 45 (1) ◽  
pp. 173-181 ◽  
Author(s):  
Georg Sedlmeier ◽  
Jonathan P. Sleeman
Keyword(s):  
Extracellular Matrix ◽  
Physical Properties ◽  
Bone Morphogenetic Protein ◽  
Bmp Signaling ◽  
Intracellular Level ◽  
Morphogenetic Protein ◽  
The Matrix ◽  
Mechanical Barrier

Given its importance in development and homeostasis, bone morphogenetic protein (BMP) signaling is tightly regulated at the extra- and intracellular level. The extracellular matrix (ECM) was initially thought to act as a passive mechanical barrier that sequesters BMPs. However, a new understanding about how the ECM plays an instructive role in regulating BMP signaling is emerging. In this mini-review, we discuss various ways in which the biochemical and physical properties of the ECM regulate BMP signaling.

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