PAR1‐stimulated platelet releasate promotes angiogenic activities of endothelial progenitor cells more potently than PAR4‐stimulated platelet releasate

Huang, Zhongwen; Miao, Xinyan; Luan, Yun; Zhu, Liqiang; Kong, Feng; Lu, Qinghua; Pernow, John; Nilsson, Gunnar; N, Li

doi:10.1111/jth.12815

Cited by 27 publications

(39 citation statements)

References 36 publications

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“…The different experimental conditions used in these studies hinder the understanding of the discrepancies obtained for each group. In this regard, some of these studies have been performed using WPs activated using either a unique stimulation time or concentration of PARs-AP [4,5,[8][9][10]17], impeding the full understanding of the dose-dependence or kinetic of the proposed differential release. Other works were performed using PRP [6,7], adding a possible contribution of the molecules physiologically circulating in the plasma.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of PAR-1 or PAR-4 promotes similar pattern of VEGF and endostatin release and pro-angiogenic responses mediated by human platelets

et al. 2015

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Background: Platelets mediate angiogenesis through the secretion of several factors, including the pro-angiogenic vascular endothelial growth factor (VEGF) and the anti-angiogenic endostatin. Although previous findings indicated that these molecules are packed into different alpha-granules and selectively released by specific stimulation of protease-activated receptor (PAR)-1 or PAR-4, recent evidences are against this hypothesis. Objectives: To elucidate the controversies about the VEGF and endostatin release and the overall angiogenic effect of PARs-stimulated platelets. Methods: VEGF and endostatin were quantified by enzyme linkedimmunosorbent assay (ELISA). Endothelial proliferation (pNPP assay), wound healing (scratch assay) and tubule formation (matrigel) of human microvascular endothelial cells (HMEC-1) and endothelial progenitor cells (EPC) were determined using supernatants from PAR-1-or PAR-4-stimulated platelets. Results: Activation of washed platelets (WPs) by PAR-1-or PAR-4-activating peptide (AP) promoted the VEGF and endostatin secretion in a concentrationdependent manner, being PAR-1-AP more potent than PAR-4-AP. The release of both molecules was abrogated by pre-incubation of platelets with PAR antagonists. Activation of platelet-rich plasma (PRP) with either PAR-1-AP or PAR-4-AP induced a significant VEGF secretion. Quantification of platelet-endostatin secretion was not possible in PRP due to the high levels of plasmatic endostatin vs. platelet content. Releasates from PAR-1-or PAR-4-activated WPs promoted similar pattern of angiogenic responses of HMEC-1 or EPC. Moreover, proliferation of HMEC-1 mediated by PAR-stimulated PRP releasates was delayed and significantly lower compared with that induced by PAR-stimulated WPs. Conclusions: Our results are in contrast with the previously described differential release of VEGF and endostatin induced by the selective PAR-1 or PAR-4 stimulation, and support the notion that while circulating endostatin accounts for the maintenance of a systemic anti-angiogenic state, locally, the release of platelet alpha-granule content promotes angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Stimulation of PAR-1 or PAR-4 promotes similar pattern of VEGF and endostatin release and pro-angiogenic responses mediated by human platelets

et al. 2015

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“…Matrigel plug assay was performed as previously described [17]. The in vivo angiogenesis protocol using a murine model of Matrigel plug subcutaneous implantation was approved by the Animal Ethics Committee of Third Military Medical University.…”

Section: Methodsmentioning

confidence: 99%

Up-Regulated Expression of Matrix Metalloproteinases in Endothelial Cells Mediates Platelet Microvesicle-Induced Angiogenesis

Sun

Feng

Cao³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Platelet microvesicles (PMVs) contribute to angiogenesis and vasculogenesis, but the mechanisms underlying these contributions have not been fully elucidated. In the present study, we investigated whether PMVs regulate the angiogenic properties of endothelial cells (ECs) via mechanisms extending beyond the transport of angiogenic regulators from platelets. Methods: In vitro Matrigel tube formation assay and in vivo Matrigel plug assay were used to evaluate the pro-angiogenic activity of PMVs. The effects of PMVs on the migration of human umbilical vein endothelial cells (HUVECs) were detected by transwell assay and wound-healing assay. Real-time PCR and western blot were conducted to examine mRNA and protein expression of pro-angiogenic factors in HUVECs. Matrix metalloproteinase (MMP) activity was assayed by gelatin zymography. Moreover, the effects of specific MMP inhibitors were tested. Results: PMVs promoted HUVEC capillary-like network formation in a dose-dependent manner. Meanwhile, PMVs dose-dependently facilitated HUVEC migration. Levels of MMP-2 and MMP-9 expression and activity were up-regulated in HUVECs stimulated with PMVs. Inhibition of MMPs decreased their pro-angiogenic and pro-migratory effects on HUVECs. Moreover, we confirmed the pro-angiogenic activity of PMVs in vivo in mice with subcutaneous implantation of Matrigel, and demonstrated that blockade of MMPs attenuated PMV-induced angiogenesis. Conclusion: The findings of our study indicate that PMVs promote angiogenesis by up-regulating MMP expression in ECs via mechanism extending beyond the direct delivery of angiogenic factors.

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“…Thrombin stimulation of both PAR-1 and PAR-4 induces selective release of platelet proangiogenic and antiangiogenic regulators. However, PAR-1 enhances vasculogenesis more potently than PAR-4 [90]. Moreover, PAR-4 activation leads to endostatin secretion [106].…”

Section: Angiogenesismentioning

confidence: 97%

“…Thrombin/ PAR-dependent pathway leads to upregulation of angiogenic factors, namely VEGF, VEGFR2, Ang-2, and along with increased ECs barrier permeability contributes to the induction of angiogenesis and seeding of secondary tumors in new distal tissues [13,90,165].…”

Section: Angiogenesismentioning

confidence: 99%

“…Thus, thrombin-activated platelets produce many substances that influence tumor proliferation, growth, invasion, and angiogenesis [13,52,82,90]. The most important of these are growth factors such as platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF), insulin-like growth factor 1 (IGF1), TGFβ, and VEGF, as well as angiogenic factors such as angiopoietin-1 (Ang-1) [13,52,87,91].…”

Section: Plateletsmentioning

confidence: 99%

See 1 more Smart Citation

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

Wojtukiewicz

Hempel

Sierko

et al. 2016

Cancer Metastasis Rev

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The association between blood coagulation and cancer development is well recognized. Thrombin, the pleiotropic enzyme best known for its contribution to fibrin formation and platelet aggregation during vascular hemostasis, may also trigger cellular events through protease-activated receptors, PAR-1 and PAR-4, leading to cancer progression. Our pioneering findings provided evidence that thrombin contributes to cancer metastasis by increasing adhesive potential of malignant cells. However, there is evidence that thrombin regulates every step of cancer dissemination: (1) cancer cell invasion, detachment from primary tumor, migration; (2) entering the blood vessel; (3) surviving in vasculature; (4) extravasation; (5) implantation in host organs. Recent studies have provided new molecular data about thrombin generation in cancer patients and the mechanisms by which thrombin contributes to transendothelial migration, platelet/tumor cell interactions, angiogenesis, and other processes. Though a great deal is known regarding the role of thrombin in cancer dissemination, there are new data for multiple thrombin-mediated events that justify devoting focus to this topic with a comprehensive approach.

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PAR1‐stimulated platelet releasate promotes angiogenic activities of endothelial progenitor cells more potently than PAR4‐stimulated platelet releasate

Cited by 27 publications

References 36 publications

Stimulation of PAR-1 or PAR-4 promotes similar pattern of VEGF and endostatin release and pro-angiogenic responses mediated by human platelets

Stimulation of PAR-1 or PAR-4 promotes similar pattern of VEGF and endostatin release and pro-angiogenic responses mediated by human platelets

Up-Regulated Expression of Matrix Metalloproteinases in Endothelial Cells Mediates Platelet Microvesicle-Induced Angiogenesis

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

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