FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2510752939> ?p ?o ?g. }

• W2510752939 endingPage "2207" @default.
• W2510752939 startingPage "2197" @default.
• W2510752939 abstract "•Arteriogenesis is mediated by coordinated action of innate immune cells•Mast cells orchestrate leukocyte function in arteriogenesis•Platelet GPIbα is decisive for shear stress-provoked mast cell activation•Shear stress-induced mast cell activation is mediated by neutrophil-derived ROS The body has the capacity to compensate for an occluded artery by creating a natural bypass upon increased fluid shear stress. How this mechanical force is translated into collateral artery growth (arteriogenesis) is unresolved. We show that extravasation of neutrophils mediated by the platelet receptor GPIbα and uPA results in Nox2-derived reactive oxygen radicals, which activate perivascular mast cells. These c-kit+/CXCR-4+ cells stimulate arteriogenesis by recruiting additional neutrophils as well as growth-promoting monocytes and T cells. Additionally, mast cells may directly contribute to vascular remodeling and vascular cell proliferation through increased MMP activity and by supplying growth-promoting factors. Boosting mast cell recruitment and activation effectively promotes arteriogenesis, thereby protecting tissue from severe ischemic damage. We thus find that perivascular mast cells are central regulators of shear stress-induced arteriogenesis by orchestrating leukocyte function and growth factor/cytokine release, thus providing a therapeutic target for treatment of vascular occlusive diseases. The body has the capacity to compensate for an occluded artery by creating a natural bypass upon increased fluid shear stress. How this mechanical force is translated into collateral artery growth (arteriogenesis) is unresolved. We show that extravasation of neutrophils mediated by the platelet receptor GPIbα and uPA results in Nox2-derived reactive oxygen radicals, which activate perivascular mast cells. These c-kit+/CXCR-4+ cells stimulate arteriogenesis by recruiting additional neutrophils as well as growth-promoting monocytes and T cells. Additionally, mast cells may directly contribute to vascular remodeling and vascular cell proliferation through increased MMP activity and by supplying growth-promoting factors. Boosting mast cell recruitment and activation effectively promotes arteriogenesis, thereby protecting tissue from severe ischemic damage. We thus find that perivascular mast cells are central regulators of shear stress-induced arteriogenesis by orchestrating leukocyte function and growth factor/cytokine release, thus providing a therapeutic target for treatment of vascular occlusive diseases. Arteries transport oxygenated blood from the heart to every individual organ of the body. Accordingly, occlusion of a major artery by thrombus formation or stenosis results in substantially reduced perfusion of distal organs, leading to ischemic damage or even necrosis of the affected tissue. Current options to treat vascular occlusive diseases such as myocardial infarction, stroke, or peripheral artery disease are percutaneous transluminal angioplasty (PTA) or bypass surgery. However, the body can create natural bypasses from pre-existing arteriolar anastomoses. This so-called arteriogenesis constitutes a tissue and even life-saving process, as it can compensate for the loss of a major peripheral or coronary artery. Promoting arteriogenesis in ischemia-related diseases may present a non-invasive alternative therapeutic approach to established clinical interventions. Arteriogenesis is a complex, multi-factorial process (Deindl and Schaper, 2005Deindl E. Schaper W. The art of arteriogenesis.Cell Biochem. Biophys. 2005; 43: 1-15Crossref PubMed Google Scholar) that involves the proliferation of endothelial cells (ECs) and smooth muscle cells (SMCs) as well as the recruitment of leukocytes, especially monocytes, which provide a variety of growth-promoting factors to the growing blood vessel (Arras et al., 1998Arras M. Ito W.D. Scholz D. Winkler B. Schaper J. Schaper W. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb.J. Clin. Invest. 1998; 101: 40-50Crossref PubMed Scopus (661) Google Scholar). It is, therefore, not surprising that the therapeutic use of single growth factors or cytokines to support arteriogenesis did not meet expectations in clinical studies. To effectively promote arteriogenesis in patients, it is important to identify the molecular mechanisms naturally triggering the process of collateral artery growth. Mast cells reside in the perivascular space of arteries (Wolf et al., 1998Wolf C. Cai W.J. Vosschulte R. Koltai S. Mousavipour D. Scholz D. Afsah-Hedjri A. Schaper W. Schaper J. Vascular remodeling and altered protein expression during growth of coronary collateral arteries.J. Mol. Cell. Cardiol. 1998; 30: 2291-2305Abstract Full Text PDF PubMed Scopus (104) Google Scholar) and produce several vasoactive substances and growth factors (Hiromatsu and Toda, 2003Hiromatsu Y. Toda S. Mast cells and angiogenesis.Microsc. Res. Tech. 2003; 60: 64-69Crossref PubMed Scopus (139) Google Scholar, Rao and Brown, 2008Rao K.N. Brown M.A. Mast cells: multifaceted immune cells with diverse roles in health and disease.Ann. N Y Acad. Sci. 2008; 1143: 83-104Crossref PubMed Scopus (209) Google Scholar), some of which have been described to contribute to arterial remodeling (Cao et al., 2003Cao R. Bråkenhielm E. Pawliuk R. Wariaro D. Post M.J. Wahlberg E. Leboulch P. Cao Y. Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2.Nat. Med. 2003; 9: 604-613Crossref PubMed Scopus (615) Google Scholar, Ito et al., 1997Ito W.D. Arras M. Winkler B. Scholz D. Schaper J. Schaper W. Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion.Circ. Res. 1997; 80: 829-837Crossref PubMed Scopus (413) Google Scholar). The functional role of these c-kit+/CXCR4+ cells in arteriogenesis is currently unclear. Moreover, how fluid shear stress, which is the driving force for arteriogenesis (Pipp et al., 2004Pipp F. Boehm S. Cai W.J. Adili F. Ziegler B. Karanovic G. Ritter R. Balzer J. Scheler C. Schaper W. Schmitz-Rixen T. Elevated fluid shear stress enhances postocclusive collateral artery growth and gene expression in the pig hind limb.Arterioscler. Thromb. Vasc. Biol. 2004; 24: 1664-1668Crossref PubMed Scopus (185) Google Scholar) and is sensed directly by vascular ECs, is translated into the activation of perivascular mast cells remains unresolved. Here we dissect the underlying mechanisms, finding a decisive role for platelets and neutrophils in this process. In particular we find that platelet receptor GPIbα-dependent and urokinase plasminogen activator (uPA)-mediated extravasation of neutrophils culminates in mast cell activation by reactive oxygen species (ROS) produced by neutrophil-expressed Nox2. Furthermore, following natural or pharmacological activation, we find that mast cells promote arteriogenesis by creating an inflammatory microenvironment essential for the recruitment of growth-promoting leukocytes. Thus, mast cells might represent a therapeutic target for the treatment of vascular occlusive diseases. To study the functional impact of mast cells in arteriogenesis, we used an experimental murine hindlimb model in which femoral artery ligation (fal) resulted in collateral artery growth in the upper leg (Figure 1A) (Limbourg et al., 2009Limbourg A. Korff T. Napp L.C. Schaper W. Drexler H. Limbourg F.P. Evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb ischemia.Nat. Protoc. 2009; 4: 1737-1746Crossref PubMed Scopus (297) Google Scholar). Our results showed that, upon fal, mast cells located in the perivascular space of collaterals became activated and gradually but specifically degranulated (Figures 1B and 1C). Moreover, treatment of mice with the mast cell activator Compound 48/80 (C48/80); the c-kit ligand stem cell factor (SCF), which triggers mast cell maturation and recruitment (Oliveira and Lukacs, 2003Oliveira S.H. Lukacs N.W. Stem cell factor: a hemopoietic cytokine with important targets in asthma.Curr. Drug Targets Inflamm. Allergy. 2003; 2: 313-318Crossref PubMed Scopus (51) Google Scholar); or diprotin A (dipA) (for protocols, see Figure 7 and Supplemental Experimental Procedures), respectively, significantly enhanced perfusion recovery upon fal (Figure 1D). DipA treatment, inhibiting dipeptidylpeptidase IV (DPPIV) activity and, thereby, retarding stroma cell-derived factor-1 (SDF-1α) degradation (Zaruba et al., 2009Zaruba M.M. Theiss H.D. Vallaster M. Mehl U. Brunner S. David R. Fischer R. Krieg L. Hirsch E. Huber B. et al.Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction.Cell Stem Cell. 2009; 4: 313-323Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar), resulted in an increased level of SDF-1α (Figure S1A) and drastically increased the number of c-kit+ cells (Figure S1B). In accordance with previous findings (McGowen et al., 2009McGowen A.L. Hale L.P. Shelburne C.P. Abraham S.N. Staats H.F. The mast cell activator compound 48/80 is safe and effective when used as an adjuvant for intradermal immunization with Bacillus anthracis protective antigen.Vaccine. 2009; 27: 3544-3552Crossref PubMed Scopus (63) Google Scholar), C48/80 treatment provoked enhanced mast cell degranulation, culminating in a drastic reduction in the numbers of detectable mast cells in the vicinity of collateral arteries (93% ± 4.6% reduction, p < 0.05). Combined administration of C48/80 and dipA further increased perfusion recovery, reaching significant values already 6 hr after fal (Figure 1D), whereas combined treatment of mice with C48/80, dipA, and SCF showed no further additive effect (Figure S1C). Simultaneous treatment of mice with dipA and the mast cell stabilizer cromolyn was performed to exclude the possibility that the positive effect of dipA was not mainly due to the mobilization of other bone marrow-derived cells also expressing the SDF-1α receptor CXCR-4 (e.g., monocytes and stem cells). Cromolyn treatment abolished the stimulating effect of dipA and impaired perfusion recovery (Figure 1D) to a similar extent as observed with single cromolyn treatment (Figure 1D), indicating that the majority of recruited cells were indeed mast cells that promoted arteriogenesis by their degranulation products. Cromolyn treatment also blocked the positive effect of C48/80 (Figure S1D). Mast cell-deficient Mcpt5-Cre+ R-DTA mice showed no reduced perfusion recovery upon the induction of arteriogenesis. Intriguingly, these mice responded neither to cromolyn nor to C48/80 treatment (Figure S1E). These data indicate that these transgenic mice were capable of compensating the lack of mast cells in arteriogenesis; yet, cromolyn as well as C48/80, specifically influenced the action of mast cells or, if at all, did not influence decisively other cells or off targets relevant for the process of collateral artery growth in wild-type mice. Matrix metalloproteinases (MMPs), which are well described to be activated by mast cell-derived proteases (Kovanen, 2007Kovanen P.T. Mast cells: multipotent local effector cells in atherothrombosis.Immunol. Rev. 2007; 217: 105-122Crossref PubMed Scopus (117) Google Scholar), degrade and remove basement membrane proteins around SMCs (Rudijanto, 2007Rudijanto A. The role of vascular smooth muscle cells on the pathogenesis of atherosclerosis.Acta Med. Indones. 2007; 39: 86-93PubMed Google Scholar) and have been shown to promote vascular remodeling in the context of arteriogenesis (Cai et al., 2000Cai W. Vosschulte R. Afsah-Hedjri A. Koltai S. Kocsis E. Scholz D. Kostin S. Schaper W. Schaper J. Altered balance between extracellular proteolysis and antiproteolysis is associated with adaptive coronary arteriogenesis.J. Mol. Cell. Cardiol. 2000; 32: 997-1011Abstract Full Text PDF PubMed Scopus (78) Google Scholar). In growing collaterals of mice treated with C48/80 + dipA, we found significantly increased MMP activity compared to saline-treated controls (Figure 2A). MCP-1 and tumor necrosis factor α (TNF-α) are two cytokines previously reported to be of major relevance for leukocyte recruitment in the process of arteriogenesis (Grundmann et al., 2005Grundmann S. Hoefer I. Ulusans S. van Royen N. Schirmer S.H. Ozaki C.K. Bode C. Piek J.J. Buschmann I. Anti-tumor necrosis factor-alpha therapies attenuate adaptive arteriogenesis in the rabbit.Am. J. Physiol. Heart Circ. Physiol. 2005; 289: H1497-H1505Crossref PubMed Scopus (49) Google Scholar, Ito et al., 1997Ito W.D. Arras M. Winkler B. Scholz D. Schaper J. Schaper W. Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion.Circ. Res. 1997; 80: 829-837Crossref PubMed Scopus (413) Google Scholar). Here mice treated with C48/80 + dipA showed significantly increased mRNA and protein levels of MCP-1 compared to saline-treated controls (Figures 2B and S2). In contrast, cromolyn treatment strongly reduced the plasma level of TNF-α as compared to saline-treated controls (Figure 2C), indicating that mast cells play a major role in providing this cytokine being relevant for leukocyte recruitment (Malaviya et al., 1996Malaviya R. Ikeda T. Ross E. Abraham S.N. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha.Nature. 1996; 381: 77-80Crossref PubMed Scopus (984) Google Scholar). Immunohistological analyses of the adductor muscle revealed significantly increased numbers of CD45+ (pan leukocyte marker) cells in the perivascular space of C48/80 + dipA-treated mice (Figure 2D). Subset analyses of recruited CD45+ cells by flow cytometry showed significantly increased levels of neutrophils (Gr-1+/CD115−) and macrophages (F4/80+) at day 1 after fal (Figures 2E and S3A) and neutrophils, macrophages, and T cells (CD3+) at day 3 after fal (Figures 2F and S3B). The latter represents a subset of leukocytes previously described to invade tissue in a TNF-α-dependent manner (Maggi et al., 2013Maggi L. Capone M. Giudici F. Santarlasci V. Querci V. Liotta F. Ficari F. Maggi E. Tonelli F. Annunziato F. Cosmi L. CD4+CD161+ T lymphocytes infiltrate Crohn’s disease-associated perianal fistulas and are reduced by anti-TNF-α local therapy.Int. Arch. Allergy Immunol. 2013; 161: 81-86Crossref PubMed Scopus (43) Google Scholar) and to be involved in arteriogenesis (Stabile et al., 2006Stabile E. Kinnaird T. la Sala A. Hanson S.K. Watkins C. Campia U. Shou M. Zbinden S. Fuchs S. Kornfeld H. et al.CD8+ T lymphocytes regulate the arteriogenic response to ischemia by infiltrating the site of collateral vessel development and recruiting CD4+ mononuclear cells through the expression of interleukin-16.Circulation. 2006; 113: 118-124Crossref PubMed Scopus (127) Google Scholar). Regarding the recruitment of subsets of CD45+ cells at day 1 and day 3 after fal, a similar although less drastic effect was observed in mice treated with C48/80 alone (Figures S3C and S3D). Treatment of primary vascular ECs and SMCs with conditioned medium of activated mast cells increased their proliferation rate (Figure S4). Moreover, fibroblast growth factor (FGF)-2 and platelet-derived growth factor (PDGF)-BB was found in mast cells located in close proximity to collateral arteries (Figure 3A). A combined administration of both growth factors previously has been described to enhance arteriogenesis (Cao et al., 2003Cao R. Bråkenhielm E. Pawliuk R. Wariaro D. Post M.J. Wahlberg E. Leboulch P. Cao Y. Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2.Nat. Med. 2003; 9: 604-613Crossref PubMed Scopus (615) Google Scholar). Mice treated with combined C48/80 + dipA revealed an increased number of Ki67+ (cell proliferation marker) vascular cells in collateral arteries (Figure 3B), which was associated with an increased luminal diameter of these blood vessels (Figure 3C). In contrast, combined treatment with cromolyn + dipA reduced the number of Ki67+ vascular cells (Figure 3B). Altogether these data suggest that mast cells promote vascular cell proliferation, not only indirectly by promoting leukocyte recruitment supplying growth-promoting factors but also by themselves representing a source of vascular growth factors. Upon ligation of the femoral artery in the upper leg, the resulting reduced perfusion of the lower leg was associated with ischemic damage, provoking increased infiltration of leukocytes and capillary sprouting (angiogenesis). Both processes are necessary for removing fibrotic and necrotic tissue. Since our data demonstrate that combined treatment of mice with C48/80 + dipA significantly increased perfusion recovery already 6 hr after fal (Figure 1D), we hypothesized that this is associated with reduced damage of the distal calf muscle (Figure S5). Histological analysis of the gastrocnemius muscle revealed almost negligible ischemic tissue damage in mice treated with C48/80 + dipA (Figure 4A). This was associated with (1) a significantly reduced infiltration of leukocytes (CD45+ cells) (Figure 4B) as well as (2) a diminished capillary sprouting, as shown by the reduced number of Ki67+ ECs (Figure 4C) and a reduced capillary-to-muscle fiber ratio (Figure S6). Interestingly, neither fal nor local application of C48/80 in the upper leg resulted in mast cell degranulation in the ipsilateral lower leg (M. gastrocnemius) (Figure 4D) or in the contralateral upper or lower leg (data not shown). These data indicate that local application of C48/80 in the upper leg did not result in systemic effects of the agent. Additionally, the data suggest that protection of tissue from ischemic damage was a result of arteriogenesis in the upper leg, but not due to degranulation of mast cells in the lower leg. Fluid shear stress, which is the driving force behind arteriogenesis, can only be sensed directly by vascular ECs, but not by perivascular cells. Hence, we asked which factors or cells may be responsible for mast cell degranulation during the initial phase of arteriogenesis. As platelets are sensors of fluid shear stress and can adhere to endothelial von Willebrand factor (vWF) under conditions of increased fluid shear stress through platelet GPIb receptor (Sadler, 2002Sadler J.E. A new name in thrombosis, ADAMTS13.Proc. Natl. Acad. Sci. USA. 2002; 99: 11552-11554Crossref PubMed Scopus (51) Google Scholar), we hypothesized that platelets or platelet-dependent reactions may be involved in transmitting molecular signals from the vascular lumen to the perivascular space. Interestingly, blockage of the platelet receptor GPIbα as well as genetic ablation of the ectodomain of GPIbα in transgenic IL4-R/Iba mice inhibited mast cell degranulation to a similar extent as cromolyn treatment (Figure 5A). Similarly, uPA deficiency or the inhibition of uPA proteolytic activity by the administration of UK122 significantly diminished mast cell degranulation (Figure 5A). We have shown previously that uPA deficiency (but not uPA receptor or tissue plasminogen activator deficiency) is associated with a reduced perfusion recovery upon fal, which was due to reduced leukocyte infiltration (day 3 after fal) (Deindl et al., 2003Deindl E. Ziegelhöffer T. Kanse S.M. Fernandez B. Neubauer E. Carmeliet P. Preissner K.T. Schaper W. Receptor-independent role of the urokinase-type plasminogen activator during arteriogenesis.FASEB J. 2003; 17: 1174-1176Crossref PubMed Scopus (46) Google Scholar). Recently, we observed a reduced reperfusion recovery upon fal when blocking the GPIbα receptor using a Fab fragment. Furthermore, the same effect was seen in GPIbα receptor-deficient IL4-R/Iba mice. Of note, our results evidenced that the GPIbα receptor is essential in arteriogenesis for (1) transient platelet interaction with collateral endothelium, (2) differential expression of vascular uPA (day 1 after fal), (3) platelet-neutrophil aggregate (PNA) formation (day 1 after fal), and (4) extravasation of leukocytes (3 days after fal) (Chandraratne et al., 2015Chandraratne S. von Bruehl M.L. Pagel J.I. Stark K. Kleinert E. Konrad I. Farschtschi S. Coletti R. Gärtner F. Chillo O. et al.Critical role of platelet glycoprotein ibα in arterial remodeling.Arterioscler. Thromb. Vasc. Biol. 2015; 35: 589-597Crossref PubMed Scopus (27) Google Scholar). Furthermore, in a model of hepatic ischemia reperfusion injury, we found endothelial-derived uPA to be essential for intravascular adherence of neutrophils. Moreover, neutrophil-derived uPA was critical for subsequent paracellular transmigration of neutrophils and, hence, extravasation (Reichel et al., 2011Reichel C.A. Uhl B. Lerchenberger M. Puhr-Westerheide D. Rehberg M. Liebl J. Khandoga A. Schmalix W. Zahler S. Deindl E. et al.Urokinase-type plasminogen activator promotes paracellular transmigration of neutrophils via Mac-1, but independently of urokinase-type plasminogen activator receptor.Circulation. 2011; 124: 1848-1859Crossref PubMed Scopus (35) Google Scholar). We therefore hypothesized that neutrophils also may play a role in arteriogenesis and may represent the missing link in mast cell activation. Indeed, inhibition of GPIbα receptor or uPA activity resulted not only in reduced mast cell activation but also in diminished neutrophil infiltration at day 1 after fal, as assessed by flow cytometry (Figures 5B and 5C). To analyze the functional relevance of neutrophils and PNA formation in more detail, we performed in vitro studies using isolated platelets and neutrophils. We found that PNA formation is a prerequisite for surface expression of uPA on neutrophils as well as for extracellular superoxide anion formation (Figures S7A–S7D). P-selectin deficiency on platelets as well as deficiency of its ligand PSGL-1 on neutrophils interfered with PNA formation and diminished uPA surface expression (Figures S7A–S7C). In addition, P-selectin deficiency of platelets prevented superoxide anion formation (Figure S7D), accounting for the relevance of platelet P-selectin for the production of neutrophil-derived ROS (Page and Pitchford, 2013Page C. Pitchford S. Neutrophil and platelet complexes and their relevance to neutrophil recruitment and activation.Int. Immunopharmacol. 2013; 17: 1176-1184Crossref PubMed Scopus (90) Google Scholar). Finally, extracellular ROS production was absent when using Nox2-deficient neutrophils for PNA formation, indicating that neutrophils are the source of superoxide anions (Figure S7D). A proposed model for neutrophil activation during arteriogenesis is shown in Figure S7E. To assess whether Nox2-derived ROS from neutrophils are relevant for mast cell degranulation during arteriogenesis, we performed further in vivo analyses. Indeed, our results showed that depletion of neutrophils by the application of 1A8 (reduction of neutrophils: 70% ± 3.7%, p < 0.05), deficiency of Nox2 (= gp91phox), as well as blocking ROS production or their function by the administration of apocynin or N-acetylcysteine (NAC) (Schulz et al., 2014Schulz R. Murzabekova G. Egemnazarov B. Kraut S. Eisele H.J. Dumitrascu R. Heitmann J. Seimetz M. Witzenrath M. Ghofrani H.A. et al.Arterial hypertension in a murine model of sleep apnea: role of NADPH oxidase 2.J. Hypertens. 2014; 32: 300-305Crossref PubMed Scopus (42) Google Scholar, Tobar et al., 2010Tobar N. Villar V. Santibanez J.F. ROS-NFkappaB mediates TGF-beta1-induced expression of urokinase-type plasminogen activator, matrix metalloproteinase-9 and cell invasion.Mol. Cell. Biochem. 2010; 340: 195-202Crossref PubMed Scopus (144) Google Scholar), respectively, blocked mast cell degranulation to a similar degree as observed in GPIbα-deficient mice (Figure 5A). To investigate whether neutrophil-derived ROS are responsible for mast cell degranulation, we created chimeric mice by transplanting bone marrow from Nox2−/− mice to wild-type mice (controlNox2−/−) and vice versa (Nox2−/−control). Compared to their corresponding control (controlcontrol), controlNox2−/− showed a significant reduction in perfusion recovery as well as mast cell degranulation, whereas Nox2−/−control revealed a significant improvement in collateral formation as compared to control (Nox2−/−Nox2−/−) (Figures 5D and 5E). To confirm that mast cells become activated by ROS derived from neutrophils, neutropenic mice were challenged with C48/80 to induce mast cell degranulation. While neutrophil depletion impaired perfusion recovery after fal, the induction of mast cell degranulation completely restored the phenotype (Figure 5F). In this study, we show that natural bypass growth is a matter of innate immunity, and we highlight the central role of mast cells in orchestrating leukocyte function in this process. In addition, we deciphered the mechanisms responsible for the translation of increased fluid shear stress to the activation of perivascular mast cells (Figure 6). Mast cells were found to reside in the perivascular space of growing collaterals (Wolf et al., 1998Wolf C. Cai W.J. Vosschulte R. Koltai S. Mousavipour D. Scholz D. Afsah-Hedjri A. Schaper W. Schaper J. Vascular remodeling and altered protein expression during growth of coronary collateral arteries.J. Mol. Cell. Cardiol. 1998; 30: 2291-2305Abstract Full Text PDF PubMed Scopus (104) Google Scholar). However, their function in arteriogenesis has never been investigated. Moreover, the mechanism by which perivascular mast cells become activated by increased mechanical load, such as fluid shear stress, has not been resolved up to now. We demonstrate that this is mediated by platelets and neutrophils and that neutrophil-derived ROS are the driving force for mast cell activation. Fluid shear stress, which stimulates arteriogenesis, is well described to induce the adherence of platelets to ECs, a process mediated by the interaction of the platelet receptor GPIbα with the endothelial vWF (Sadler, 2002Sadler J.E. A new name in thrombosis, ADAMTS13.Proc. Natl. Acad. Sci. USA. 2002; 99: 11552-11554Crossref PubMed Scopus (51) Google Scholar). We recently demonstrated that platelet receptor GPIbα is essential for the transient interaction of platelets to collateral endothelium, PNA formation, and extravasation of leukocytes during arteriogenesis (Chandraratne et al., 2015Chandraratne S. von Bruehl M.L. Pagel J.I. Stark K. Kleinert E. Konrad I. Farschtschi S. Coletti R. Gärtner F. Chillo O. et al.Critical role of platelet glycoprotein ibα in arterial remodeling.Arterioscler. Thromb. Vasc. Biol. 2015; 35: 589-597Crossref PubMed Scopus (27) Google Scholar). Here we show that platelet receptor GPIbα is particularly relevant for neutrophil extravasation. We demonstrate that PNA formation through platelet P-selectin and neutrophil PSGL-1 is associated with uPA release to the neutrophil cell surface, paving the way for leukocyte infiltration. Moreover, we found that PNA formation is a prerequisite for neutrophil Nox2-dependent superoxide anion release. As the deficiency or inhibition of uPA resulted in diminished neutrophil extravasation and mast cell degranulation, it is fair to deduce that the activation of neutrophils through interaction with platelets not only drives extravasation of these cells via uPA but also promotes mast cell activation via the release of neutrophil superoxide anions. This conclusion is endorsed by our findings showing (1) a rescue of the impaired reperfusion recovery and mast cell degranulation observed in Nox2−/− mice by the transplantation of bone marrow isolated from wild-type mice, and (2) restored perfusion in neutropenic mice by the induction of mast cell degranulation. These in vivo data are affirmed by in vitro findings showing that ROS stimulate mast cell activation (Gan et al., 2015Gan X. Xing D. Su G. Li S. Luo C. Irwin M.G. Xia Z. Li H. Hei Z. Propofol attenuates small intestinal ischemia reperfusion injury through inhibiting NADPH oxidase mediated mast cell activation.Oxid. Med. Cell. Longev. 2015; 2015: 167014Crossref PubMed Scopus (33) Google Scholar) as well as by our results showing that activated neutrophils induce mast cell degranulation (Figure S7F). Together, these data indicate that the intravascular, shear stress-dependent activation of platelets and PNA formation triggers the production of effectors, such as ROS, that serve to transmit the locally initiated signal to proximal perivascular sites where mast cell degranulation is initiated. Interestingly enough, platelet activation, uPA-mediated neutrophil extravasation, as well as mast cell activation recently were shown to contribute to reperfusion injury due to revascularization or organ transplantation (Chang et al., 2014Chang J.C. Leung J. Tang T. Holzknecht Z.E. Hartwig M.G. Duane Davis R. Parker W. Abraham S.N. Lin S.S. Cromolyn ameliorates acute and chronic injury in a rat lung transplant model.Journal Heart Lung Transplant. 2014; 33: 749-757Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, Egashira et al., 2013Egashira Y. Suzuki Y. Azuma Y. Takagi T. Mishiro K. Sugitani S. Tsuruma K. Shimazawa M. Yoshimura S. Kashimata M. et al.The growth factor progranulin attenuates neuronal injury induced by cerebral ischemia-reperfusion through the suppression of neutrophil recruitment.J. Neuroinflammation. 2013; 10: 105Crossref PubMed Scopus (99) Google Scholar, Köhler et al., 2011Köhler D. Straub A. Weissmüller T. Faigle M. Bender S. Lehmann R. Wendel H.P. Kurz J. Walter U. Zacharowski K. Rosenberger P. Phosphorylation of vasodilator-stimulated phosphoprotein prevents platelet-neutrophil complex formation and dampens myocardial ischemia-reperfusion injury.Circulation. 2011; 123: 2579-2590Crossref PubMed Scopus (47) Google Scholar, Reichel et al., 2011Reichel C.A. Uhl B. Lerchenberger M. Puhr-Westerheide D. Rehberg M. Liebl J. Khandoga A. Schmalix W. Zahler S. Dei" @default.
• W2510752939 created "2016-09-16" @default.
• W2510752939 creator A5008888080 @default.
• W2510752939 creator A5012059860 @default.
• W2510752939 creator A5013277128 @default.
• W2510752939 creator A5020909162 @default.
• W2510752939 creator A5029867519 @default.
• W2510752939 creator A5035848091 @default.
• W2510752939 creator A5037724494 @default.
• W2510752939 creator A5038589044 @default.
• W2510752939 creator A5043709743 @default.
• W2510752939 creator A5046908944 @default.
• W2510752939 creator A5048716653 @default.
• W2510752939 creator A5054393619 @default.
• W2510752939 creator A5060738562 @default.
• W2510752939 creator A5062092776 @default.
• W2510752939 creator A5067046766 @default.
• W2510752939 creator A5069421991 @default.
• W2510752939 creator A5071272326 @default.
• W2510752939 creator A5075858508 @default.
• W2510752939 creator A5079837507 @default.
• W2510752939 creator A5083473328 @default.
• W2510752939 date "2016-08-01" @default.
• W2510752939 modified "2023-10-16" @default.
• W2510752939 title "Perivascular Mast Cells Govern Shear Stress-Induced Arteriogenesis by Orchestrating Leukocyte Function" @default.
• W2510752939 cites W1213978291 @default.
• W2510752939 cites W1526883212 @default.
• W2510752939 cites W1968596406 @default.
• W2510752939 cites W1970017835 @default.
• W2510752939 cites W1970653879 @default.
• W2510752939 cites W1970900504 @default.
• W2510752939 cites W1988123774 @default.
• W2510752939 cites W1990268036 @default.
• W2510752939 cites W1996734641 @default.
• W2510752939 cites W2007982994 @default.
• W2510752939 cites W2010914305 @default.
• W2510752939 cites W2013561823 @default.
• W2510752939 cites W2014368942 @default.
• W2510752939 cites W2017502688 @default.
• W2510752939 cites W2020546717 @default.
• W2510752939 cites W2027207867 @default.
• W2510752939 cites W2033314236 @default.
• W2510752939 cites W2036324226 @default.
• W2510752939 cites W2055027929 @default.
• W2510752939 cites W2061443292 @default.
• W2510752939 cites W2067336260 @default.
• W2510752939 cites W2076496958 @default.
• W2510752939 cites W2079362390 @default.
• W2510752939 cites W2082595130 @default.
• W2510752939 cites W2084208522 @default.
• W2510752939 cites W2088919776 @default.
• W2510752939 cites W2092016122 @default.
• W2510752939 cites W2096448538 @default.
• W2510752939 cites W2100190333 @default.
• W2510752939 cites W2111614540 @default.
• W2510752939 cites W2114480478 @default.
• W2510752939 cites W2114650909 @default.
• W2510752939 cites W2118273159 @default.
• W2510752939 cites W2118653134 @default.
• W2510752939 cites W2119533880 @default.
• W2510752939 cites W2127854619 @default.
• W2510752939 cites W2133346775 @default.
• W2510752939 cites W2134446651 @default.
• W2510752939 cites W2145162853 @default.
• W2510752939 cites W2146263464 @default.
• W2510752939 cites W2146845949 @default.
• W2510752939 cites W2163993647 @default.
• W2510752939 cites W2180665610 @default.
• W2510752939 cites W2216127328 @default.
• W2510752939 doi "https://doi.org/10.1016/j.celrep.2016.07.040" @default.
• W2510752939 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/27524614" @default.
• W2510752939 hasPublicationYear "2016" @default.
• W2510752939 type Work @default.
• W2510752939 sameAs 2510752939 @default.
• W2510752939 citedByCount "48" @default.
• W2510752939 countsByYear W25107529392017 @default.
• W2510752939 countsByYear W25107529392018 @default.
• W2510752939 countsByYear W25107529392019 @default.
• W2510752939 countsByYear W25107529392020 @default.
• W2510752939 countsByYear W25107529392021 @default.
• W2510752939 countsByYear W25107529392022 @default.
• W2510752939 countsByYear W25107529392023 @default.
• W2510752939 crossrefType "journal-article" @default.
• W2510752939 hasAuthorship W2510752939A5008888080 @default.
• W2510752939 hasAuthorship W2510752939A5012059860 @default.
• W2510752939 hasAuthorship W2510752939A5013277128 @default.
• W2510752939 hasAuthorship W2510752939A5020909162 @default.
• W2510752939 hasAuthorship W2510752939A5029867519 @default.
• W2510752939 hasAuthorship W2510752939A5035848091 @default.
• W2510752939 hasAuthorship W2510752939A5037724494 @default.
• W2510752939 hasAuthorship W2510752939A5038589044 @default.
• W2510752939 hasAuthorship W2510752939A5043709743 @default.
• W2510752939 hasAuthorship W2510752939A5046908944 @default.
• W2510752939 hasAuthorship W2510752939A5048716653 @default.
• W2510752939 hasAuthorship W2510752939A5054393619 @default.
• W2510752939 hasAuthorship W2510752939A5060738562 @default.
• W2510752939 hasAuthorship W2510752939A5062092776 @default.
• W2510752939 hasAuthorship W2510752939A5067046766 @default.

• next