Complementary Effects of Extracellular Nucleotides and Platelet-derived Extracts on Angiogenesis of Vasa Vasorum Endothelial Cells in Vitro and Subcutaneous Matrigel Plugs in Vivo

Overview

Journal Vasc Cell

Date 2011 Feb 26

PMID 21349161

Citations 5

Authors

Mark Roedersheimer

Hala Nijmeh

Nana Burns

Asya A Sidiakova

Kurt R Stenmark

Evgenia V Gerasimovskaya

Affiliations

Soon will be listed here.

Abstract

Background: Platelets contribute to vascular homeostasis and angiogenesis through the release of multiple growth factors, cytokines and nucleotides, such as ATP and ADP. Recent reports have demonstrated a marked growth-promoting effect of total platelet extracts and selected platelet growth factors on therapeutic angiogenesis. However, since endogenous adenine nucleotides are rapidly degraded during the platelet isolation and storage, we examined whether supplementing a platelet-derived extract with exogenous adenine nucleotides would augment their pro-angiogenic effects.

Methods: Pulmonary artery vasa vasorum endothelial cells (VVEC) were used to examine the effects of dialyzed platelet-derived soluble extracts and extracellular adenine nucleotides on proliferation, migration and tube formation. In addition, an in vivo Matrigel plug assay was used to examine the effects of platelet extracts and adenine nucleotides on neovascularization of plugs subcutaneously placed in 50 ICR mice. The number of vascular structures in Matrigel plugs were evaluated by histological and statistical methods.

Results: Platelet extracts (6.4-64 μg/ml) significantly induced DNA synthesis and at a concentration of 64 μg/ml had a biphasic effect on VVEC proliferation (an increase at 48 hrs followed by a decrease at 60 hrs). Stimulation of VVEC with platelet extracts also significantly (up to several-fold) increased cell migration and tube formation on Matrigel. Stimulation of VVEC with extracellular ATP (100 μM) dramatically (up to ten-fold) increased migration and tube formation on Matrigel; however, no significant effects on cell proliferation were observed. We also found that ATP moderately diminished platelet extract-induced VVEC proliferation (48 hrs) and migration, but potentiated tube formation. Neither ATP, or a mixture of non-hydrolyzable nucleotides (ATPγS, ADPβS, MeSATP, MeSADP) induced vascularization of Matrigel plugs subcutaneously injected in mice, however, the combination of these nucleotides with platelet extracts dramatically increased the number of functional capillaries in the Matrigel plugs.

Conclusion: Data from this study suggest that platelet-derived growth factors and extracellular nucleotides represent important regulatory signals for angiogenesis. Supplementation of platelet extracts with exogenous adenine nucleotides may reveal new possibilities for therapeutic angiogenesis and tissue regeneration approaches.

Citing Articles

P2Y Purinergic Receptors, Endothelial Dysfunction, and Cardiovascular Diseases.

Strassheim D, Verin A, Batori R, Nijmeh H, Burns N, Kovacs-Kasa A Int J Mol Sci. 2020; 21(18).

PMID: 32962005 PMC: 7555413. DOI: 10.3390/ijms21186855.

Solving the Measurement Problem and then Steppin' Out over the Line Riding the Rarest Italian: Crossing the Streams to Retrieve Stable Bioactivity in Majorana Bound States of Dialy zed Human Platelet Lysates.

Roedersheimer M Open Neurol J. 2015; 9:32-44.

PMID: 26191092 PMC: 4503829. DOI: 10.2174/1874205X01509010032.

Synergistic effect of bone marrow-derived mesenchymal stem cells and platelet-rich plasma in streptozotocin-induced diabetic rats.

Lian Z, Yin X, Li H, Jia L, He X, Yan Y Ann Dermatol. 2014; 26(1):1-10.

PMID: 24648680 PMC: 3956772. DOI: 10.5021/ad.2014.26.1.1.

New insights regarding the regulation of chemotaxis by nucleotides, adenosine, and their receptors.

Corriden R, Insel P Purinergic Signal. 2012; 8(3):587-98.

PMID: 22528684 PMC: 3360098. DOI: 10.1007/s11302-012-9311-x.

Human platelet-rich plasma- and extracellular matrix-derived peptides promote impaired cutaneous wound healing in vivo.

Demidova-Rice T, Wolf L, Deckenback J, Hamblin M, Herman I PLoS One. 2012; 7(2):e32146.

PMID: 22384158 PMC: 3285658. DOI: 10.1371/journal.pone.0032146.

References

Langer H, May A, Daub K, Heinzmann U, Lang P, Schumm M . Adherent platelets recruit and induce differentiation of murine embryonic endothelial progenitor cells to mature endothelial cells in vitro. Circ Res. 2005; 98(2):e2-10. DOI: 10.1161/01.RES.0000201285.87524.9e. View

Davie N, Gerasimovskaya E, Hofmeister S, Richman A, Jones P, Reeves J . Pulmonary artery adventitial fibroblasts cooperate with vasa vasorum endothelial cells to regulate vasa vasorum neovascularization: a process mediated by hypoxia and endothelin-1. Am J Pathol. 2006; 168(6):1793-807. PMC: 1606613. DOI: 10.2353/ajpath.2006.050754. View

de Boer H, Verseyden C, Ulfman L, Zwaginga J, Bot I, Biessen E . Fibrin and activated platelets cooperatively guide stem cells to a vascular injury and promote differentiation towards an endothelial cell phenotype. Arterioscler Thromb Vasc Biol. 2006; 26(7):1653-9. DOI: 10.1161/01.ATV.0000222982.55731.f1. View

Browder T, Folkman J . The hemostatic system as a regulator of angiogenesis. J Biol Chem. 2000; 275(3):1521-4. DOI: 10.1074/jbc.275.3.1521. View

Wang L, Karlsson L, Moses S, Hultgardh-Nilsson A, Andersson M, Borna C . P2 receptor expression profiles in human vascular smooth muscle and endothelial cells. J Cardiovasc Pharmacol. 2002; 40(6):841-53. DOI: 10.1097/00005344-200212000-00005. View

Kaczmarek E, Erb L, Koziak K, Jarzyna R, Wink M, Guckelberger O . Modulation of endothelial cell migration by extracellular nucleotides: involvement of focal adhesion kinase and phosphatidylinositol 3-kinase-mediated pathways. Thromb Haemost. 2005; 93(4):735-42. PMC: 2830093. DOI: 10.1160/TH04-09-0576. View

Schallmoser K, Strunk D . Preparation of pooled human platelet lysate (pHPL) as an efficient supplement for animal serum-free human stem cell cultures. J Vis Exp. 2009; (32). PMC: 3164065. DOI: 10.3791/1523. View

English D, Welch Z, Kovala A, Harvey K, Volpert O, Brindley D . Sphingosine 1-phosphate released from platelets during clotting accounts for the potent endothelial cell chemotactic activity of blood serum and provides a novel link between hemostasis and angiogenesis. FASEB J. 2000; 14(14):2255-65. DOI: 10.1096/fj.00-0134com. View

Bambace N, Levis J, Holmes C . The effect of P2Y-mediated platelet activation on the release of VEGF and endostatin from platelets. Platelets. 2010; 21(2):85-93. DOI: 10.3109/09537100903470298. View

10.

Roedersheimer M, West J, Huffer W, Harral J, Benedict J . A bone-derived mixture of TGF beta-superfamily members forms a more mature vascular network than bFGF or TGF-beta 2 in vivo. Angiogenesis. 2006; 8(4):327-38. DOI: 10.1007/s10456-005-9022-9. View

11.

Manegold P, Hutter J, Pahernik S, Messmer K, Dellian M . Platelet-endothelial interaction in tumor angiogenesis and microcirculation. Blood. 2003; 101(5):1970-6. DOI: 10.1182/blood.V101.5.1970. View

12.

Woodward H, Anwar A, Riddle S, Taraseviciene-Stewart L, Fragoso M, Stenmark K . PI3K, Rho, and ROCK play a key role in hypoxia-induced ATP release and ATP-stimulated angiogenic responses in pulmonary artery vasa vasorum endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2009; 297(5):L954-64. PMC: 2777489. DOI: 10.1152/ajplung.00038.2009. View

13.

Burnstock G . Purine and pyrimidine receptors. Cell Mol Life Sci. 2007; 64(12):1471-83. PMC: 11149472. DOI: 10.1007/s00018-007-6497-0. View

14.

Daub K, Langer H, Seizer P, Stellos K, May A, Goyal P . Platelets induce differentiation of human CD34+ progenitor cells into foam cells and endothelial cells. FASEB J. 2006; 20(14):2559-61. DOI: 10.1096/fj.06-6265fje. View

15.

Lyubchenko T, Woodward H, Veo K, Burns N, Nijmeh H, Liubchenko G . P2Y1 and P2Y13 purinergic receptors mediate Ca2+ signaling and proliferative responses in pulmonary artery vasa vasorum endothelial cells. Am J Physiol Cell Physiol. 2010; 300(2):C266-75. PMC: 3043637. DOI: 10.1152/ajpcell.00237.2010. View

16.

Valls M, Cronstein B, Carmen Montesinos M . Adenosine receptor agonists for promotion of dermal wound healing. Biochem Pharmacol. 2008; 77(7):1117-24. PMC: 2671632. DOI: 10.1016/j.bcp.2008.11.002. View

17.

Jain R . Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001; 7(9):987-9. DOI: 10.1038/nm0901-987. View

18.

Italiano Jr J, Richardson J, Patel-Hett S, Battinelli E, Zaslavsky A, Short S . Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood. 2007; 111(3):1227-33. PMC: 2214735. DOI: 10.1182/blood-2007-09-113837. View

19.

Woulfe D, Yang J, Brass L . ADP and platelets: the end of the beginning. J Clin Invest. 2001; 107(12):1503-5. PMC: 200202. DOI: 10.1172/JCI13361. View

20.

Ralevic V, Burnstock G . Receptors for purines and pyrimidines. Pharmacol Rev. 1998; 50(3):413-92. View