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APOE ε4-specific associations of VEGF gene family expression with cognitive aging and Alzheimer's disease.
Moore AM, Mahoney E, Dumitrescu L, De Jager PL, Koran MEI, Petyuk VA, Robinson RA, Ruderfer DM, Cox NJ, Schneider JA, Bennett DA, Jefferson AL, Hohman TJ
(2020) Neurobiol Aging 87: 18-25
MeSH Terms: Aged, Aged, 80 and over, Aging, Apolipoprotein E4, Cognitive Aging, Cognitive Dysfunction, Female, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Male, Neovascularization, Physiologic, Neuropilin-1, Vascular Endothelial Growth Factor A
Show Abstract · Added March 30, 2020
Literature suggests vascular endothelial growth factor A (VEGFA) is protective among those at highest risk for Alzheimer's disease (AD). Apolipoprotein E (APOE) ε4 allele carriers represent a highly susceptible population for cognitive decline, and VEGF may confer distinct protection among APOE-ε4 carriers. We evaluated interactions between cortical expression of 10 VEGF gene family members and APOE-ε4 genotype to clarify which VEGF genes modify the association between APOE-ε4 and cognitive decline. Data were obtained from the Religious Orders Study and Rush Memory and Aging Project (N = 531). Linear regression assessed interactions on global cognition. VEGF genes NRP1 and VEGFA interacted with APOE-ε4 on cognitive performance (p.fdr < 0.05). Higher NRP1 expression correlated with worse outcomes among ε4 carriers but better outcomes among ε4 noncarriers, suggesting NRP1 modifies the risk for poor cognitive scores based on APOE-ε4 status. NRP1 regulates angiogenesis, and literature suggests vessels in APOE-ε4 brains are more prone to leaking, perhaps placing young vessels at risk for ischemia. Results suggest that future therapeutics targeting brain angiogenesis should also consider ε4 allele status.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms
Identification of a pro-angiogenic functional role for FSP1-positive fibroblast subtype in wound healing.
Saraswati S, Marrow SMW, Watch LA, Young PP
(2019) Nat Commun 10: 3027
MeSH Terms: Actins, Animals, Bone Marrow Transplantation, Calcium-Binding Proteins, Cell Differentiation, Disease Models, Animal, Fibroblasts, Fibrosis, Green Fluorescent Proteins, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myocardial Infarction, Myocardium, Neovascularization, Physiologic, S100 Calcium-Binding Protein A4, Transplantation Chimera, Wound Healing
Show Abstract · Added March 24, 2020
Fibrosis accompanying wound healing can drive the failure of many different organs. Activated fibroblasts are the principal determinants of post-injury pathological fibrosis along with physiological repair, making them a difficult therapeutic target. Although activated fibroblasts are phenotypically heterogeneous, they are not recognized as distinct functional entities. Using mice that express GFP under the FSP1 or αSMA promoter, we characterized two non-overlapping fibroblast subtypes from mouse hearts after myocardial infarction. Here, we report the identification of FSP1-GFP cells as a non-pericyte, non-hematopoietic fibroblast subpopulation with a predominant pro-angiogenic role, characterized by in vitro phenotypic/cellular/ultrastructural studies and in vivo granulation tissue formation assays combined with transcriptomics and proteomics. This work identifies a fibroblast subtype that is functionally distinct from the pro-fibrotic αSMA-expressing myofibroblast subtype. Our study has the potential to shift our focus towards viewing fibroblasts as molecularly and functionally heterogeneous and provides a paradigm to approach treatment for organ fibrosis.
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The Size of Intramedullary Fixation Affects Endochondral-Mediated Angiogenesis During Fracture Repair.
Yuasa M, Saito M, Blum DM, Hysong AA, Egawa S, Uppuganti S, Yoshii T, Okawa A, Schwartz HS, Moore-Lotridge SN, Nyman JS, Schoenecker JG
(2019) J Orthop Trauma 33: e385-e393
MeSH Terms: Animals, Bone Nails, Bony Callus, Cartilage, Fracture Fixation, Intramedullary, Fracture Healing, Male, Mice, Mice, Inbred C57BL, Neovascularization, Physiologic, Prosthesis Design, Vascular Endothelial Growth Factor A
Show Abstract · Added March 25, 2020
OBJECTIVES - To explore the effect of intramedullary pin size on the biology of a healing fracture, specifically endochondral angiogenesis. We hypothesized that fracture fixation with a smaller pin would permit greater interfragmentary strain resulting in increased total amount of vascular endothelial growth factor within the callus and greater angiogenesis compared to fixation with a larger pin.
METHODS - Transverse mid-shaft femur fractures in 8-week-old mice were fixed with either a 23-gauge (G) or 30-G pin. Differences in interfragmentary strain at the fracture site were estimated between cohorts. A combination of histology, gene expression, serial radiography, and microcomputed tomography with and without vascular contrast agent were used to assess fracture healing and vascularity for each cohort.
RESULTS - Larger soft-tissue callus formation increased vascular endothelial growth factor-A expression, and a corresponding increase in vascular volume was observed in the higher strain, 30-G cohort. Radiographic analysis demonstrated earlier hard callus formation with greater initial interfragmentary strain, similar rates of union between pin size cohorts, yet delayed callus remodeling in mice with the larger pin size.
CONCLUSIONS - These findings suggest that the stability conferred by an intramedullary nail influences endochondral angiogenesis at the fracture.
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12 MeSH Terms
Exploring the potential of polyurethane-based soft foam as cell-free scaffold for soft tissue regeneration.
Gerges I, Tamplenizza M, Martello F, Recordati C, Martelli C, Ottobrini L, Tamplenizza M, Guelcher SA, Tocchio A, Lenardi C
(2018) Acta Biomater 73: 141-153
MeSH Terms: Adipose Tissue, Animals, Mice, NIH 3T3 Cells, Neovascularization, Physiologic, Polyurethanes, Regeneration, Tissue Scaffolds
Show Abstract · Added March 20, 2020
Reconstructive treatment after trauma and tumor resection would greatly benefit from an effective soft tissue regeneration. The use of cell-free scaffolds for adipose tissue regeneration in vivo is emerging as an attractive alternative to tissue-engineered constructs, since this approach avoids complications due to cell manipulation and lack of synchronous vascularization. In this study, we developed a biodegradable polyurethane-based scaffold for soft tissue regeneration, characterized by an exceptional combination between softness and resilience. Exploring the potential as a cell-free scaffold required profound understanding of the impact of its intrinsic physico-chemical properties on the biological performance in vivo. We investigated the effect of the scaffold's hydrophilic character, degradation kinetics, and internal morphology on (i) the local inflammatory response and activation of MGCs (foreign body response); (ii) its ability to promote rapid vascularisation, cell infiltration and migration through the scaffold over time; and (iii) the grade of maturation of the newly formed tissue into vascularized soft tissue in a murine model. The study revealed that soft tissue regeneration in vivo proceeded by gradual infiltration of undifferentiated mesenchymal cells though the periphery toward the center of the scaffold, where the rapid formation of a functional and well-formed vascular network supported cell viability overtime.
STATEMENT OF SIGNIFICANCE - Exploring the potential of polyurethane-based soft foam as cell-free scaffold for soft tissue regeneration. In this work, we address the unmet need for synthetic functional soft tissue substitutes that provide adequate biological and mechanical support to soft tissue. We developed a series of flexible cross-linked polyurethane copolymer scaffolds with remarkable fatigue-resistance and tunable physico-chemical properties for soft tissue regeneration in vivo. Accordingly, we could extend the potential of this class of biomaterials, which was so far confined for bone and osteochondral tissue regeneration, to other types of connective tissue.
Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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Patient-Specific iPSC-Derived Endothelial Cells Uncover Pathways that Protect against Pulmonary Hypertension in BMPR2 Mutation Carriers.
Gu M, Shao NY, Sa S, Li D, Termglinchan V, Ameen M, Karakikes I, Sosa G, Grubert F, Lee J, Cao A, Taylor S, Ma Y, Zhao Z, Chappell J, Hamid R, Austin ED, Gold JD, Wu JC, Snyder MP, Rabinovitch M
(2017) Cell Stem Cell 20: 490-504.e5
MeSH Terms: Base Sequence, Bone Morphogenetic Protein 4, Bone Morphogenetic Protein Receptors, Type II, Cell Adhesion, Cell Movement, Cell Shape, Cell Survival, Endothelial Cells, Gene Editing, Gene Expression Regulation, Heterozygote, Humans, Hypertension, Pulmonary, Induced Pluripotent Stem Cells, Mutation, Neovascularization, Physiologic, Phosphorylation, Sequence Analysis, RNA, Signal Transduction, Smad Proteins, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added February 21, 2017
In familial pulmonary arterial hypertension (FPAH), the autosomal dominant disease-causing BMPR2 mutation is only 20% penetrant, suggesting that genetic variation provides modifiers that alleviate the disease. Here, we used comparison of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from three families with unaffected mutation carriers (UMCs), FPAH patients, and gender-matched controls to investigate this variation. Our analysis identified features of UMC iPSC-ECs related to modifiers of BMPR2 signaling or to differentially expressed genes. FPAH-iPSC-ECs showed reduced adhesion, survival, migration, and angiogenesis compared to UMC-iPSC-ECs and control cells. The "rescued" phenotype of UMC cells was related to an increase in specific BMPR2 activators and/or a reduction in inhibitors, and the improved cell adhesion could be attributed to preservation of related signaling. The improved survival was related to increased BIRC3 and was independent of BMPR2. Our findings therefore highlight protective modifiers for FPAH that could help inform development of future treatment strategies.
Copyright © 2017 Elsevier Inc. All rights reserved.
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21 MeSH Terms
Local Delivery of PHD2 siRNA from ROS-Degradable Scaffolds to Promote Diabetic Wound Healing.
Martin JR, Nelson CE, Gupta MK, Yu F, Sarett SM, Hocking KM, Pollins AC, Nanney LB, Davidson JM, Guelcher SA, Duvall CL
(2016) Adv Healthc Mater 5: 2751-2757
MeSH Terms: Animals, Cell Proliferation, Diabetes Mellitus, Hypoxia-Inducible Factor-Proline Dioxygenases, Male, Neovascularization, Physiologic, Procollagen-Proline Dioxygenase, RNA, Small Interfering, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species, Tissue Engineering, Tissue Scaffolds, Wound Healing
Show Abstract · Added March 14, 2018
Small interfering RNA (siRNA) delivered from reactive oxygen species-degradable tissue engineering scaffolds promotes diabetic wound healing in rats. Porous poly(thioketal-urethane) scaffolds implanted in diabetic wounds locally deliver siRNA that inhibits the expression of prolyl hydroxylase domain protein 2, thereby increasing the expression of progrowth genes and increasing vasculature, proliferating cells, and tissue development in diabetic wounds.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Determination of the CD148-Interacting Region in Thrombospondin-1.
Takahashi K, Sumarriva K, Kim R, Jiang R, Brantley-Sieders DM, Chen J, Mernaugh RL, Takahashi T
(2016) PLoS One 11: e0154916
MeSH Terms: Animals, Binding Sites, Cell Proliferation, Cells, Cultured, Endothelial Cells, Gene Knockdown Techniques, Humans, Immunoblotting, Immunoprecipitation, Mice, Inbred C57BL, Neovascularization, Physiologic, Peptide Fragments, Protein Tyrosine Phosphatases, Receptor-Like Protein Tyrosine Phosphatases, Class 3, Thrombospondin 1
Show Abstract · Added April 26, 2017
CD148 is a transmembrane protein tyrosine phosphatase that is expressed in multiple cell types, including vascular endothelial cells and duct epithelial cells. Previous studies have shown a prominent role of CD148 to reduce growth factor signals and suppress cell proliferation and transformation. Further, we have recently shown that thrombospondin-1 (TSP1) serves as a functionally important ligand for CD148. TSP1 has multiple structural elements and interacts with various cell surface receptors that exhibit differing effects. In order to create the CD148-specific TSP1 fragment, here we investigated the CD148-interacting region in TSP1 using a series of TSP1 fragments and biochemical and biological assays. Our results demonstrate that: 1) CD148 binds to the 1st type 1 repeat in TSP1; 2) Trimeric TSP1 fragments that contain the 1st type repeat inhibit cell proliferation in A431D cells that stably express wild-type CD148 (A431D/CD148wt cells), while they show no effects in A431D cells that lack CD148 or express a catalytically inactive form of CD148. The anti-proliferative effect of the TSP1 fragment in A431D/CD148wt cells was largely abolished by CD148 knockdown and antagonized by the 1st, but not the 2nd and 3rd, type 1 repeat fragment. Furthermore, the trimeric TSP1 fragments containing the 1st type repeat increased the catalytic activity of CD148 and reduced phospho-tyrosine contents of EGFR and ERK1/2, defined CD148 substrates. These effects were not observed in the TSP1 fragments that lack the 1st type 1 repeat. Last, we demonstrate that the trimeric TSP1 fragment containing the 1st type 1 repeat inhibits endothelial cell proliferation in culture and angiogenesis in vivo. These effects were largely abolished by CD148 knockdown or deficiency. Collectively, these findings indicate that the 1st type 1 repeat interacts with CD148, reducing growth factor signals and inhibiting epithelial or endothelial cell proliferation and angiogenesis.
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15 MeSH Terms
VEGFB/VEGFR1-Induced Expansion of Adipose Vasculature Counteracts Obesity and Related Metabolic Complications.
Robciuc MR, Kivelä R, Williams IM, de Boer JF, van Dijk TH, Elamaa H, Tigistu-Sahle F, Molotkov D, Leppänen VM, Käkelä R, Eklund L, Wasserman DH, Groen AK, Alitalo K
(2016) Cell Metab 23: 712-24
MeSH Terms: Adipose Tissue, Animals, Mice, Inbred C57BL, Neovascularization, Physiologic, Obesity, Vascular Endothelial Growth Factor B, Vascular Endothelial Growth Factor Receptor-2
Show Abstract · Added May 5, 2016
Impaired angiogenesis has been implicated in adipose tissue dysfunction and the development of obesity and associated metabolic disorders. Here, we report the unexpected finding that vascular endothelial growth factor B (VEGFB) gene transduction into mice inhibits obesity-associated inflammation and improves metabolic health without changes in body weight or ectopic lipid deposition. Mechanistically, the binding of VEGFB to VEGF receptor 1 (VEGFR1, also known as Flt1) activated the VEGF/VEGFR2 pathway and increased capillary density, tissue perfusion, and insulin supply, signaling, and function in adipose tissue. Furthermore, endothelial Flt1 gene deletion enhanced the effect of VEGFB, activating the thermogenic program in subcutaneous adipose tissue, which increased the basal metabolic rate, thus preventing diet-induced obesity and related metabolic complications. In obese and insulin-resistant mice, Vegfb gene transfer, together with endothelial Flt1 gene deletion, induced weight loss and mitigated the metabolic complications, demonstrating the therapeutic potential of the VEGFB/VEGFR1 pathway.
Copyright © 2016 Elsevier Inc. All rights reserved.
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7 MeSH Terms
Safety and angiogenic effects of systemic gene delivery of a modified erythropoietin.
de Lucas Cerrillo AM, Bond WS, Rex TS
(2015) Gene Ther 22: 365-73
MeSH Terms: Animals, CHO Cells, Cells, Cultured, Cricetinae, Cricetulus, Endothelium, Vascular, Erythropoiesis, Erythropoietin, Gene Transfer Techniques, Humans, Mice, Mice, Inbred C57BL, Mutation, Missense, Neovascularization, Physiologic, Retinal Vessels
Show Abstract · Added April 2, 2019
Erythropoietin (EPO) is critical for red blood cell production and is also an effective neuroprotective agent. However, it may contribute to pathological angiogenesis. Here we investigate the angiogenic potential of EPO and a mutant form with attenuated erythropoietic activity, EPO-R76E, on primary human retinal microvascular endothelial cells (HRMECs) and in the adult retina. Assays of death, proliferation and tube formation were performed on HRMECs exposed to EPO, EPO-R76E or media alone. Postnatal day-9 wild-type mice were injected intramuscularly with adeno-associated virus vectors expressing either enhanced green fluorescent protein or EpoR76E. At 3 months, levels of EPO-R76E in the eye were quantified, and the health of the retinal vasculature was assessed by fluorescein angiography and isolectin immunolabeling. Immunohistochemistry, histology and electroretinogram (ERG) assessments were performed as measures of retinal health. Neither EPO nor EPO-R76E induced proliferation or tube formation in HRMECs under the conditions used. EPO-R76E decreased HRMEC death in a dose-dependent manner. Long-term systemic gene delivery of EPO-R76E was safe in terms of retinal vasculature, histology and the ERG in vivo. Our results show that EPO-R76E can block HRMEC death, consistent with its role in erythropoiesis and neuroprotection. In addition, long-term gene delivery of EPO-R76E is safe in the adult retina.
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Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways.
Wang S, Amato KR, Song W, Youngblood V, Lee K, Boothby M, Brantley-Sieders DM, Chen J
(2015) Mol Cell Biol 35: 1299-313
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Cell Proliferation, Cells, Cultured, Endothelial Cells, Gene Deletion, Human Umbilical Vein Endothelial Cells, Humans, Mechanistic Target of Rapamycin Complex 2, Mice, Multiprotein Complexes, Neovascularization, Physiologic, Phosphorylation, Protein Kinase C-alpha, Proto-Oncogene Proteins c-akt, Rapamycin-Insensitive Companion of mTOR Protein, Regulatory-Associated Protein of mTOR, Signal Transduction, TOR Serine-Threonine Kinases, Vascular Endothelial Growth Factor A
Show Abstract · Added February 15, 2016
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates a diverse array of cellular processes, including cell growth, survival, metabolism, and cytoskeleton dynamics. mTOR functions in two distinct complexes, mTORC1 and mTORC2, whose activities and substrate specificities are regulated by complex specific cofactors, including Raptor and Rictor, respectively. Little is known regarding the relative contribution of mTORC1 versus mTORC2 in vascular endothelial cells. Using mouse models of Raptor or Rictor gene targeting, we discovered that Rictor ablation inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation and assembly in vitro and angiogenesis in vivo, whereas the loss of Raptor had only a modest effect on endothelial cells (ECs). Mechanistically, the loss of Rictor reduced the phosphorylation of AKT, protein kinase Cα (PKCα), and NDRG1 without affecting the mTORC1 pathway. In contrast, the loss of Raptor increased the phosphorylation of AKT despite inhibiting the phosphorylation of S6K1, a direct target of mTORC1. Reconstitution of Rictor-null cells with myristoylated AKT (Myr-AKT) rescued vascular assembly in Rictor-deficient endothelial cells, whereas PKCα rescued proliferation defects. Furthermore, tumor neovascularization in vivo was significantly decreased upon EC-specific Rictor deletion in mice. These data indicate that mTORC2 is a critical signaling node required for VEGF-mediated angiogenesis through the regulation of AKT and PKCα in vascular endothelial cells.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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21 MeSH Terms