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1.
Int J Mol Sci ; 25(12)2024 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-38928082

RESUMO

Vascular remodeling is a very general feature related to angiogenesis and arteriogenesis, which are involved in neovascularization processes [...].


Assuntos
Neovascularização Patológica , Neovascularização Fisiológica , Remodelação Vascular , Humanos , Animais , Neovascularização Patológica/patologia , Neovascularização Patológica/metabolismo , Angiogênese
2.
Biomedicines ; 12(2)2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38397911

RESUMO

Tissue ischemia, caused by the blockage of blood vessels, can result in substantial damage and impaired tissue performance. Information regarding the functional contribution of the complement system in the context of ischemia and angiogenesis is lacking. To investigate the influence of complement activation and depletion upon femoral artery ligation (FAL), Cobra venom factor (CVF) (that functionally resembles C3b, the activated form of complement component C3) was applied in mice in comparison to control mice. Seven days after induction of muscle ischemia through FAL, gastrocnemius muscles of mice were excised and subjected to (immuno-)histological analyses. H&E and apoptotic cell staining (TUNEL) staining revealed a significant reduction in ischemic tissue damage in CVF-treated mice compared to controls. The control mice, however, exhibited a significantly higher capillary-to-muscle fiber ratio and a higher number of proliferating endothelial cells (CD31+/CD45-/BrdU+). The total number of leukocytes (CD45+) substantially decreased in CVF-treated mice versus control mice. Moreover, the CVF-treated group displayed a shift towards the M2-like anti-inflammatory and regenerative macrophage phenotype (CD68+/MRC1+). In conclusion, our findings suggest that treatment with CVF leads to reduced ischemic tissue damage along with decreased leukocyte recruitment but increased numbers of M2-like polarized macrophages, thereby enhancing tissue regeneration, repair, and healing.

3.
Int J Mol Sci ; 24(16)2023 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-37629019

RESUMO

Increasing evidence suggests that lymphocytes play distinct roles in inflammation-induced tissue remodeling and tissue damage. Arteriogenesis describes the growth of natural bypasses from pre-existing collateral arteries. This process compensates for the loss of artery function in occlusive arterial diseases. The role of innate immune cells is widely understood in the process of arteriogenesis, whereas the role of lymphocytes remains unclear and is the subject of the present study. To analyze the role of lymphocytes, we induced arteriogenesis in recombination activating gene-1 (Rag1) knockout (KO) mice by unilateral ligation of the femoral artery. The lack of functional lymphocytes in Rag1 KO mice resulted in reduced perfusion recovery as shown by laser Doppler imaging. Additionally, immunofluorescence staining revealed a reduced vascular cell proliferation along with a smaller inner luminal diameter in Rag1 KO mice. The perivascular macrophage polarization around the growing collateral arteries was shifted to more pro-inflammatory M1-like polarized macrophages. Together, these data suggest that lymphocytes are crucial for arteriogenesis by modulating perivascular macrophage polarization.


Assuntos
Artéria Femoral , Inflamação , Animais , Camundongos , Proliferação de Células , Extremidade Inferior , Camundongos Knockout
4.
Cells ; 11(17)2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36078113

RESUMO

The innate immune system is the first line of defense against bacterial and viral infections and sterile inflammation through the recognition of pathogen-associated molecular patterns (PAMPs) as well as danger-associated molecular patterns (DAMPs) by pathogen-recognition receptors (PRRs), and produces proinflammatory and antiviral cytokines and chemokines [...].


Assuntos
Imunidade Inata , Alarminas , Infecções Bacterianas/imunologia , Citocinas , Humanos , Receptores de Reconhecimento de Padrão , Viroses/imunologia
5.
Int J Mol Sci ; 23(15)2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35955584

RESUMO

Arteriogenesis, the growth of natural bypass blood vessels, can compensate for the loss of arteries caused by vascular occlusive diseases. Accordingly, it is a major goal to identify the drugs promoting this innate immune system-driven process in patients aiming to save their tissues and life. Here, we studied the impact of the Cobra venom factor (CVF), which is a C3-like complement-activating protein that induces depletion of the complement in the circulation in a murine hind limb model of arteriogenesis. Arteriogenesis was induced in C57BL/6J mice by femoral artery ligation (FAL). The administration of a single dose of CVF (12.5 µg) 24 h prior to FAL significantly enhanced the perfusion recovery 7 days after FAL, as shown by Laser Doppler imaging. Immunofluorescence analyses demonstrated an elevated number of proliferating (BrdU+) vascular cells, along with an increased luminal diameter of the grown collateral vessels. Flow cytometric analyses of the blood samples isolated 3 h after FAL revealed an elevated number of neutrophils and platelet-neutrophil aggregates. Giemsa stains displayed augmented mast cell recruitment and activation in the perivascular space of the growing collaterals 8 h after FAL. Seven days after FAL, we found more CD68+/MRC-1+ M2-like polarized pro-arteriogenic macrophages around growing collaterals. These data indicate that a single dose of CVF boosts arteriogenesis by catalyzing the innate immune reactions, relevant for collateral vessel growth.


Assuntos
Venenos Elapídicos , Artéria Femoral , Animais , Venenos Elapídicos/metabolismo , Venenos Elapídicos/farmacologia , Artéria Femoral/metabolismo , Membro Posterior/irrigação sanguínea , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/fisiologia
6.
Cells ; 11(9)2022 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-35563796

RESUMO

γδ T cells, a small subset of T cells in blood, play a substantial role in influencing immunoregulatory and inflammatory processes. The functional impact of γδ T cells on angiogenesis in ischemic muscle tissue has never been reported and is the topic of the present work. Femoral artery ligation (FAL) was used to induce angiogenesis in the lower leg of γδ T cell depleted mice and wildtype and isotype antibody-treated control groups. Gastrocnemius muscle tissue was harvested 3 and 7 days after FAL and assessed using (immuno-)histological analyses. Hematoxylin and Eosin staining showed an increased area of tissue damage in γδ T cell depleted mice 7 days after FAL. Impaired angiogenesis was demonstrated by lower capillary to muscle fiber ratio and decreased number of proliferating endothelial cells (CD31+/BrdU+). γδ T cell depleted mice showed an increased number of total leukocytes (CD45+), neutrophils (MPO+) and neutrophil extracellular traps (NETs) (MPO+/CitH3+), without changes in the neutrophils to NETs ratio. Moreover, the depletion resulted in a higher macrophage count (DAPI/CD68+) caused by an increase in inflammatory M1-like macrophages (CD68+/MRC1-). Altogether, we show that depletion of γδ T cells leads to increased accumulation of leukocytes and M1-like macrophages, along with impaired angiogenesis.


Assuntos
Células Endoteliais , Isquemia , Animais , Células Endoteliais/patologia , Isquemia/patologia , Contagem de Leucócitos , Macrófagos/patologia , Camundongos , Músculo Esquelético/patologia
7.
Int J Mol Sci ; 22(24)2021 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-34948041

RESUMO

Vascular occlusive diseases such myocardial infarction, peripheral artery disease of the lower extremities, or stroke still represent a substantial health burden worldwide [...].


Assuntos
Arteriopatias Oclusivas/diagnóstico , Neovascularização Patológica/diagnóstico , Neovascularização Fisiológica , Indutores da Angiogênese , Arteriopatias Oclusivas/genética , Arteriopatias Oclusivas/metabolismo , Circulação Sanguínea , Diagnóstico Precoce , Humanos , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo
8.
Int J Mol Sci ; 22(21)2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34769229

RESUMO

Strain-related differences in arteriogenesis in inbred mouse strains have already been studied excessively. However, these analyses missed evaluating the mouse strain-related differences in ischemia-induced angiogenic capacities. With the present study, we wanted to shed light on the different angiogenic potentials and the associated leukocyte infiltration of C57BL/6J and SV-129 mice to facilitate the comparison of angiogenesis-related analyses between these strains. For the induction of angiogenesis, we ligated the femoral artery in 8-12-week-old male C57BL/6J and SV-129 mice and performed (immuno-) histological analyses on the ischemic gastrocnemius muscles collected 24 h or 7 days after ligation. As evidenced by hematoxylin and eosin staining, C57BL/6J mice showed reduced tissue damage but displayed an increased capillary-to-muscle fiber ratio and an elevated number of proliferating capillaries (CD31+/BrdU+ cells) compared to SV-129 mice, thus showing improved angiogenesis. Regarding the associated leukocyte infiltration, we found increased numbers of neutrophils (MPO+ cells), NETs (MPO+/CitH3+/DAPI+), and macrophages (CD68+ cells) in SV-129 mice, whereas macrophage polarization (MRC1- vs. MRC1+) and total leukocyte infiltration (CD45+ cells) did not differ between the mouse strains. In summary, we show increased ischemia-induced angiogenic capacities in C57BL/6J mice compared to SV-129 mice, with the latter showing aggravated tissue damage, inflammation, and impaired angiogenesis.


Assuntos
Membro Posterior , Isquemia/metabolismo , Macrófagos/metabolismo , Músculo Esquelético , Neovascularização Fisiológica , Neutrófilos/metabolismo , Animais , Membro Posterior/irrigação sanguínea , Membro Posterior/metabolismo , Masculino , Camundongos , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Especificidade da Espécie
9.
J Vis Exp ; (175)2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34661568

RESUMO

Arteriogenesis strongly depends on leukocyte and platelet recruitment to the perivascular space of growing collateral vessels. The standard approach for analyzing collateral arteries and leukocytes in arteriogenesis is ex vivo (immuno-) histological methodology. However, this technique does not allow the measurement of dynamic processes such as blood flow, shear stress, cell-cell interactions, and particle velocity. This paper presents a protocol to monitor in vivo processes in growing collateral arteries during arteriogenesis utilizing intravital imaging. The method described here is a reliable tool for dynamics measurement and offers a high-contrast analysis with minimal photo-cytotoxicity, provided by multiphoton excitation microscopy. Prior to analyzing growing collateral arteries, arteriogenesis was induced in the adductor muscle of mice by unilateral ligation of the femoral artery. After the ligation, the preexisting collateral arteries started to grow due to increased shear stress. Twenty-four hours after surgery, the skin and subcutaneous fat above the collateral arteries were removed, constructing a pocket for further analyses. To visualize blood flow and immune cells during in vivo imaging, CD41-fluorescein isothiocyanate (FITC) (platelets) and CD45-phycoerythrin (PE) (leukocytes) antibodies were injected intravenously (i.v.) via a catheter placed in the tail vein of a mouse. This article introduces intravital multiphoton imaging as an alternative or in vivo complementation to the commonly used static ex vivo (immuno-) histological analyses to study processes relevant for arteriogenesis. In summary, this paper describes a novel and dynamic in vivo method to investigate immune cell trafficking, blood flow, and shear stress in a hindlimb model of arteriogenesis, which enhances evaluation possibilities notably.


Assuntos
Leucócitos , Neovascularização Fisiológica , Animais , Artéria Femoral , Membro Posterior , Microscopia Intravital , Camundongos
10.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502391

RESUMO

Extracellular Cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, is released from cells upon hypoxia and cold-stress. The overall absence of extra- and intracellular CIRP is associated with increased angiogenesis, most likely induced through influencing leukocyte accumulation. The aim of the present study was to specifically characterize the role of eCIRP in ischemia-induced angiogenesis together with the associated leukocyte recruitment. For analyzing eCIRPs impact, we induced muscle ischemia via femoral artery ligation (FAL) in mice in the presence or absence of an anti-CIRP antibody and isolated the gastrocnemius muscle for immunohistological analyses. Upon eCIRP-depletion, mice showed increased capillary/muscle fiber ratio and numbers of proliferating endothelial cells (CD31+/CD45-/BrdU+). This was accompanied by a reduction of total leukocyte count (CD45+), neutrophils (MPO+), neutrophil extracellular traps (NETs) (MPO+CitH3+), apoptotic area (ascertained via TUNEL assay), and pro-inflammatory M1-like polarized macrophages (CD68+/MRC1-) in ischemic muscle tissue. Conversely, the number of regenerative M2-like polarized macrophages (CD68+/MRC1+) was elevated. Altogether, we observed that eCIRP depletion similarly affected angiogenesis and leukocyte recruitment as described for the overall absence of CIRP. Thus, we propose that eCIRP is mainly responsible for modulating angiogenesis via promoting pro-angiogenic microenvironmental conditions in muscle ischemia.


Assuntos
Isquemia/patologia , Neovascularização Fisiológica/fisiologia , Proteínas de Ligação a RNA/metabolismo , Animais , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Inflamação/patologia , Isquemia/metabolismo , Contagem de Leucócitos , Leucócitos/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos da Linhagem 129 , Músculos/metabolismo , Neutrófilos/metabolismo , Proteínas de Ligação a RNA/fisiologia
11.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071589

RESUMO

The complement system is a potent inflammatory trigger, activator, and chemoattractant for leukocytes, which play a crucial role in promoting angiogenesis. However, little information is available about the influence of the complement system on angiogenesis in ischemic muscle tissue. To address this topic and analyze the impact of the complement system on angiogenesis, we induced muscle ischemia in complement factor C3 deficient (C3-/-) and wildtype control mice by femoral artery ligation (FAL). At 24 h and 7 days after FAL, we isolated the ischemic gastrocnemius muscles and investigated them by means of (immuno-)histological analyses. C3-/- mice showed elevated ischemic damage 7 days after FAL, as evidenced by H&E staining. In addition, angiogenesis was increased in C3-/- mice, as demonstrated by increased capillary/muscle fiber ratio and increased proliferating endothelial cells (CD31+/BrdU+). Moreover, our results showed that the total number of leukocytes (CD45+) was increased in C3-/- mice, which was based on an increased number of neutrophils (MPO+), neutrophil extracellular trap formation (MPO+/CitH3+), and macrophages (CD68+) displaying a shift toward an anti-inflammatory and pro-angiogenic M2-like polarized phenotype (CD68+/MRC1+). In summary, we show that the deficiency of complement factor C3 increased neutrophil and M2-like polarized macrophage accumulation in ischemic muscle tissue, contributing to angiogenesis.


Assuntos
Capilares/fisiopatologia , Complemento C3/deficiência , Isquemia/fisiopatologia , Leucócitos/metabolismo , Músculo Esquelético/fisiopatologia , Animais , Capilares/metabolismo , Complemento C3/genética , Modelos Animais de Doenças , Imunofluorescência/métodos , Humanos , Isquemia/genética , Ativação de Macrófagos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Infiltração de Neutrófilos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo
12.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34086056

RESUMO

Peripheral nerve injury can cause debilitating disease and immune cell-mediated destruction of the affected nerve. While the focus has been on the nerve-regenerative response, the effect of loss of innervation on lymph node function is unclear. Here, we show that the popliteal lymph node (popLN) receives direct neural input from the sciatic nerve and that sciatic denervation causes lymph node expansion. Loss of sympathetic, adrenergic tone induces the expression of IFN-γ in LN CD8 T cells, which is responsible for LN expansion. Surgery-induced IFN-γ expression and expansion can be rescued by ß2 adrenergic receptor agonists but not sensory nerve agonists. These data demonstrate the mechanisms governing the pro-inflammatory effect of loss of direct adrenergic input on lymph node function.


Assuntos
Adrenérgicos/metabolismo , Interferon gama/metabolismo , Linfonodos/patologia , Traumatismos dos Nervos Periféricos/patologia , Animais , Antígenos/imunologia , Autoimunidade , Axotomia , Linfócitos T CD8-Positivos/imunologia , Denervação , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Nervo Isquiático/imunologia , Nervo Isquiático/patologia , Transdução de Sinais
13.
Biomedicines ; 9(4)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33916904

RESUMO

Cold-inducible RNA-binding protein (CIRP) is an intracellular RNA-chaperone and extracellular promoter of inflammation, which is increasingly expressed and released under conditions of hypoxia and cold stress. The functional relevance of CIRP for angiogenesis and regeneration of ischemic muscle tissue has never been investigated and is the topic of the present study. We investigated the role of CIRP employing CIRP deficient mice along with a hindlimb model of ischemia-induced angiogenesis. 1 and 7 days after femoral artery ligation or sham operation, gastrocnemius muscles of CIRP-deficient and wildtype mice were isolated and processed for (immuno-) histological analyses. CIRP deficient mice showed decreased ischemic tissue damage as evidenced by Hematoxylin and Eosin staining, whereas angiogenesis was enhanced as demonstrated by increased capillary/muscle fiber ratio and number of proliferating endothelial (CD31+/BrdU+) cells on day 7 after surgery. Moreover, CIRP deficiency resulted in a reduction of total leukocyte count (CD45+), neutrophils (myeloperoxidase, MPO+), neutrophil extracellular traps (NETs) (MPO+/CitH3+), and inflammatory M1-like polarized macrophages (CD68+/MRC1-), whereas the number of tissue regenerating M2-like polarized macrophages (CD68+/MRC1-) was increased in ischemic tissue samples. In summary, we show that the absence of CIRP ameliorates angiogenesis and regeneration of ischemic muscle tissue, most likely by influencing macrophage polarization in direction to regenerative M2-like macrophages.

14.
Front Physiol ; 11: 576736, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240100

RESUMO

Background: RNase A (the bovine equivalent to human RNase 1) and RNase 5 (angiogenin) are two closely related ribonucleases. RNase 5 is described as a powerful angiogenic factor. Whether RNase A shares the same angiogenic characteristic, or interferes with vessel growth as demonstrated for arteriogenesis, has never been investigated and is the topic of this present study. Methods and Results: To investigate whether RNase A shows a pro- or anti-angiogenic effect, we employed a murine hindlimb model, in which femoral artery ligation (FAL) results in arteriogenesis in the upper leg, and, due to provoked ischemia, in angiogenesis in the lower leg. C57BL/6J male mice underwent unilateral FAL, whereas the contralateral leg was sham operated. Two and seven days after the surgery and intravenous injection of RNase A (50 µg/kg dissolved in saline) or saline (control), the gastrocnemius muscles of mice were isolated from the lower legs for (immuno-) histological analyses. Hematoxylin and Eosin staining evidenced that RNase A treatment resulted in a higher degree of ischemic tissue damage. This was, however, associated with reduced angiogenesis, as evidenced by a reduced capillary/muscle fiber ratio. Moreover, RNase A treatment was associated with a significant reduction in leukocyte infiltration as shown by CD45+ (pan-leukocyte marker), Ly6G+ or MPO+ (neutrophils), MPO+/CitH3 + [neutrophil extracellular traps (NETs)], and CD68+ (macrophages) staining. CD68/MRC1 double staining revealed that RNase A treated mice showed a reduced percentage of M1-like polarized (CD68+/MRC1-) macrophages whereas the percentage of M2-like polarized (CD68+/MRC1+) macrophages was increased. Conclusion: In contrast to RNase 5, RNase A interferes with angiogenesis, which is linked to reduced leukocyte infiltration and NET formation.

15.
Cells ; 9(6)2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32531915

RESUMO

Arteriogenesis, also frequently called collateral formation or even therapeutic angiogenesis, comprises those processes that lead to the formation and growth of collateral blood vessels that can act as natural bypasses to restore blood flow to distal tissues in occluded arteries [...].


Assuntos
Artérias/fisiopatologia , Neovascularização Fisiológica/fisiologia , Humanos
16.
Int J Mol Sci ; 21(10)2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32438752

RESUMO

Arteriogenesis, the growth of a natural bypass from pre-existing arteriolar collaterals, is an endogenous mechanism to compensate for the loss of an artery. Mechanistically, this process relies on a locally and temporally restricted perivascular infiltration of leukocyte subpopulations, which mediate arteriogenesis by supplying growth factors and cytokines. Currently, the state-of-the-art method to identify and quantify these leukocyte subpopulations in mouse models is immunohistology. However, this is a time consuming procedure. Here, we aimed to develop an optimized protocol to identify and quantify leukocyte subpopulations by means of flow cytometry in adductor muscles containing growing collateral arteries. For that purpose, adductor muscles of murine hindlimbs were isolated at day one and three after induction of arteriogenesis, enzymatically digested, and infiltrated leukocyte subpopulations were identified and quantified by flow cytometry, as exemplary shown for neutrophils and macrophages (defined as CD45+/CD11b+/Ly6G+ and CD45+/CD11b+/F4/80+ cells, respectively). In summary, we show that flow cytometry is a suitable method to identify and quantify leukocyte subpopulations in muscle tissue, and provide a detailed protocol. Flow cytometry constitutes a timesaving tool compared to histology, which might be used in addition for precise localization of leukocytes in tissue samples.


Assuntos
Citometria de Fluxo/métodos , Leucócitos/patologia , Doença Arterial Periférica/diagnóstico , Animais , Modelos Animais de Doenças , Membro Posterior/patologia , Imuno-Histoquímica , Masculino , Camundongos Endogâmicos C57BL
17.
Int J Mol Sci ; 21(10)2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32466112

RESUMO

This Special Issue enqueues a series of publications dealing with arteriogenesis, which is the growth of a natural bypass from pre-existing arteriolar connections, as defined by Wolfgang Schaper, Werner Risau and Ramon Munoz-Chapuli in the late nineties of the last century [...].


Assuntos
Neovascularização Fisiológica , Animais , Artérias/metabolismo , Artérias/fisiologia , Humanos
18.
Cells ; 9(4)2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276492

RESUMO

Collateral artery growth (arteriogenesis) involves the proliferation of vascular endothelial cells (ECs) and smooth muscle cells (SMCs). Whereas the proliferation of ECs is directly related to shear stress, the driving force for arteriogenesis, little is known about the mechanisms of SMC proliferation. Here we investigated the functional relevance of the potassium channels KV1.3 and KCa3.1 for SMC proliferation in arteriogenesis. Employing a murine hindlimb model of arteriogenesis, we found that blocking KV1.3 with PAP-1 or KCa3.1. with TRAM-34, both interfered with reperfusion recovery after femoral artery ligation as shown by Laser-Doppler Imaging. However, only treatment with PAP-1 resulted in a reduced SMC proliferation. qRT-PCR results revealed an impaired downregulation of α smooth muscle-actin (αSM-actin) and a repressed expression of fibroblast growth factor receptor 1 (Fgfr1) and platelet derived growth factor receptor b (Pdgfrb) in growing collaterals in vivo and in primary murine arterial SMCs in vitro under KV1.3. blockade, but not when KCa3.1 was blocked. Moreover, treatment with PAP-1 impaired the mRNA expression of the cell cycle regulator early growth response-1 (Egr1) in vivo and in vitro. Together, these data indicate that KV1.3 but not KCa3.1 contributes to SMC proliferation in arteriogenesis.


Assuntos
Circulação Colateral/fisiologia , Miócitos de Músculo Liso/fisiologia , Canais de Potássio/fisiologia , Animais , Proliferação de Células , Humanos , Masculino , Camundongos , Neovascularização Fisiológica
19.
Front Cell Dev Biol ; 8: 619221, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33392206

RESUMO

Upon vascular injury, tissue damage, ischemia, or microbial infection, intracellular material such as nucleic acids and histones is liberated and comes into contact with the vessel wall and circulating blood cells. Such "Danger-associated molecular patterns" (DAMPs) may thus have an enduring influence on the inflammatory defense process that involves leukocyte recruitment and wound healing reactions. While different species of extracellular RNA (exRNA), including microRNAs and long non-coding RNAs, have been implicated to influence inflammatory processes at different levels, recent in vitro and in vivo work has demonstrated a major impact of ribosomal exRNA as a prominent DAMP on various steps of leukocyte recruitment within the innate immune response. This includes the induction of vascular hyper-permeability and vasogenic edema by exRNA via the activation of the "vascular endothelial growth factor" (VEGF) receptor-2 system, as well as the recruitment of leukocytes to the inflamed endothelium, the M1-type polarization of inflammatory macrophages, or the role of exRNA as a pro-thrombotic cofactor to promote thrombosis. Beyond sterile inflammation, exRNA also augments the docking of bacteria to host cells and the subsequent microbial invasion. Moreover, upon vessel occlusion and ischemia, the shear stress-induced release of exRNA initiates arteriogenesis (i.e., formation of natural vessel bypasses) in a multistep process that resembles leukocyte recruitment. Although exRNA can be counteracted for by natural circulating RNase1, under the conditions mentioned, only the administration of exogenous, thermostable, non-toxic RNase1 provides an effective and safe therapeutic regimen for treating the damaging activities of exRNA. It remains to be investigated whether exRNA may also influence viral infections (including COVID-19), e.g., by supporting the interaction of host cells with viral particles and their subsequent invasion. In fact, as a consequence of the viral infection cycle, massive amounts of exRNA are liberated, which can provoke further tissue damage and enhance virus dissemination. Whether the application of RNase1 in this scenario may help to limit the extent of viral infections like COVID-19 and impact on leukocyte recruitment and emigration steps in immune defense in order to limit the extent of associated cardiovascular diseases remains to be studied.

20.
Int J Mol Sci ; 20(24)2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31817879

RESUMO

Arteriogenesis is an intricate process in which increased shear stress in pre-existing arteriolar collaterals induces blood vessel expansion, mediated via endothelial cell activation, leukocyte recruitment and subsequent endothelial and smooth muscle cell proliferation. Extracellular RNA (eRNA), released from stressed cells or damaged tissue under pathological conditions, has recently been discovered to be liberated from endothelial cells in response to increased shear stress and to promote collateral growth. Until now, eRNA has been shown to enhance coagulation and inflammation by inducing cytokine release, leukocyte recruitment, and endothelial permeability, the latter being mediated by vascular endothelial growth factor (VEGF) signaling. In the context of arteriogenesis, however, eRNA has emerged as a transmitter of shear stress into endothelial activation, mediating the sterile inflammatory process essential for collateral remodeling, whereby the stimulatory effects of eRNA on the VEGF signaling axis seem to be pivotal. In addition, eRNA might influence subsequent steps of the arteriogenesis cascade as well. This article provides a comprehensive overview of the beneficial effects of eRNA during arteriogenesis, laying the foundation for further exploration of the connection between the damaging and non-damaging effects of eRNA in the context of cardiovascular occlusive diseases and of sterile inflammation.


Assuntos
Artérias/crescimento & desenvolvimento , Células Endoteliais/citologia , Miócitos de Músculo Liso/citologia , Neovascularização Fisiológica , RNA/metabolismo , Animais , Artérias/metabolismo , Células Endoteliais/metabolismo , Humanos , Miócitos de Músculo Liso/metabolismo , RNA/genética , Transdução de Sinais
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