**4. Conclusions**

This chapter presented the water quality monitoring, control, and management framework for a collaborative control and management of agricultural drainage water for addressing the issue of prevalent water crisis. The framework leverages individual networked farms and streams into an integrated water management mechanism. Such a monitoring system should enable each farm to share information about its drainage flow with neighbor networks, for example, with a drainage bay network, which can then process the information for timely treatment, disposal, or reuse of the drainage.

*Water Sustainability through Drainage Reuse in Agriculture – A Case for Collaborative Wireless... DOI: http://dx.doi.org/10.5772/intechopen.106486*

To implement the drainage management, the architecture of the WQMCM framework comprises various modules. Modules for a drainage bay network include neighbor linking model, and predictive models for drainage and pollutant dynamics, whereas, for a farm network, a decision support model is used to ascertain the reusability of the predicted drainage event. The overall functionality of the framework is explored in terms of stages of learning, training, and testing. In the learning stage, neighbor linking model is used to determine the correlation of events in various farm networks with the events received in the drainage bay by the drainage network. The model results in identifying linked and un-linked farm networks by using a combination of geographical filtering and linear regression methods. For the linked networks, training dataset is acquired to provide for the development of the predictive models for drainage dynamics and nitrate losses. When the drainage network has learned the environment and the predictive models for individual farms, it is brought into a testing stage. In this stage, neighbor event information is firstly interpreted using developed neighbor linking lists and then, in case of a linked neighbor, used to predict drainage dynamics. These predicted values are transmitted by a drainage network to other farms and stream networks so that they can take a decision for the reuse, disposal, or conservation of the expected drainage.

#### **Acknowledgements**

I would like to express my gratitude to Dr. Nick Harris and Dr. Geoff Merrett (University of Southampton, United Kingdom), and also acknowledge Dr. Mark Rivers and Dr. Keith Smetten (University of Western Australia, Australia) for their support and valuable advice on this research work.


*4.6. Western Blot Analysis*

Protein expression of LAT1, LAT2, p-4EBP1 (Thr-37/46), and p-S6k1 (Thr-389) was examined by Western blotting. An aliquot of 20 µg of total protein was subject to electrophoresis then transferred to nitrocellulose membrane. After blocking, the membranes were probed with anti-human antibody against LAT1, LAT2, p-4EBP1 (Thr-37/46), or p-S6k1 (Thr-389) and followed by corresponding biotinylate conjugated secondary antibodies. Antibodies against LAT1 and LAT2 were obtained from Santa Cruz Biotechnology; p-4EBP1 (Thr-37/46) and p-S6k1 (Thr-389) antibodies were purchased from Cell Signaling Technology (Danvers, MA). The bound antibody was visualized with an enhanced chemiluminescent detection kit (Thermo Scientific). β-actin expression was used as loading control for each sample. The band densities were scanned and analyzed by Alpha Imager software (Alpha Innotech Corporation, CA, USA).


**5. Conclusions**

Genetic modification increases the therapeutic efficacy of stem cells by improving their survival, enhancement of paracrine activity and by supporting their angiomyogenic differentiation (Tang et al. 2004). A combined cell and gene therapy approach reverses the deteriorating function of the infarcted heart (Mangi et al. 2003; Matsumoto et al. 2005) and offers an extended and localized expression of the transgene product. From the clinical standpoint, the strength of stem cell therapy and gene therapy approaches lies in their combined application to achieve stable therapeutic benefits. The viability and persistence of the genetically modified stem cells and their derivative graft in the heart can be significantly enhanced by restoration of regional blood flow *via* biological bypass surgery which is achieved by neovascularization of the infarcted heart. The new emerging pro-angiogenic role of angiopoietin-1 independent of VEGF, in addition to its well recognized participation in the angiogenic cascade as a maturation factor, makes angiopoietin-1 as a growth factor of choice for ex-vivo stem cell based gene therapy which can be used independently or in combination with VEGF to support angiomyogenic recovery of the infarcted heart.

#### **6. Acknowledgements**

This work was supported by National Institutes of Health Grants #R37-HL074272;HL-080686;HL-087246(M.A) and HL-087288;HL-089535; HL106190-01 (Kh.H.H).

#### **7. References**

al. 2008). Besides, we also opted to replace Vegf with survival signaling molecule Akt to support survival of the genetically modified mesenchymal stem cells (Jiang et al. 2006). Our choice of transgene combination of angiopoietin-1 and Akt achieved maximum beneficial effects in terms of donor stem cell survival and angiomyogenic repair of the infarcted heart. More importantly, the therapeutic benefits in terms of cell graft survival, stability of newly formed blood vessels and global cardiac function were stable for up to 3 months (Shujia et al. 2008). A more recent study has used sendai viral vector for transduction of mesenchymal stem cells, however, it remains difficult to see the advantages of mesenchymal stem cells modified with sendai vector harboring human angiopoietin-1 gene (Piao, Wang et al.)

Genetic modification increases the therapeutic efficacy of stem cells by improving their survival, enhancement of paracrine activity and by supporting their angiomyogenic differentiation (Tang et al. 2004). A combined cell and gene therapy approach reverses the deteriorating function of the infarcted heart (Mangi et al. 2003; Matsumoto et al. 2005) and offers an extended and localized expression of the transgene product. From the clinical standpoint, the strength of stem cell therapy and gene therapy approaches lies in their combined application to achieve stable therapeutic benefits. The viability and persistence of the genetically modified stem cells and their derivative graft in the heart can be significantly enhanced by restoration of regional blood flow *via* biological bypass surgery which is achieved by neovascularization of the infarcted heart. The new emerging pro-angiogenic role of angiopoietin-1 independent of VEGF, in addition to its well recognized participation in the angiogenic cascade as a maturation factor, makes angiopoietin-1 as a growth factor of choice for ex-vivo stem cell based gene therapy which can be used independently or in

combination with VEGF to support angiomyogenic recovery of the infarcted heart.

080686;HL-087246(M.A) and HL-087288;HL-089535; HL106190-01 (Kh.H.H).

manner. *Hypertension* 56(3): 477-83.

regeneration in vivo. *Mol Ther* 10(5): 844-54.

This work was supported by National Institutes of Health Grants #R37-HL074272;HL-

Abdel-Malak NA, Mofarrahi M, Mayaki D, Khachigian LM, Hussain SN. (2009). Early

migration, and differentiation. *Arterioscler Thromb Vasc Biol* 29(2): 209-16. Abdel-Malak NA, Srikant CB, Kristof AS, Magder SA, Di Battista JA, Hussain SN. (2008).

1-dependent autocrine production of interleukin-8. *Blood* 111(8): 4145-54. Ahmad S, Cudmore MJ, Wang K, Hewett P, Potluri R, Fujisawa T, Ahmed A. (2010).

Armulik A, Abramsson A, Betsholtz C. (2005). Endothelial/pericyte interactions. *Circ Res*

Arsic N, Zacchigna S, Zentilin L, Ramirez-Correa G, Pattarini L, Salvi A, Sinagra G, Giacca

growth response-1 regulates angiopoietin-1-induced endothelial cell proliferation,

Angiopoietin-1 promotes endothelial cell proliferation and migration through AP-

Angiopoietin-1 induces migration of monocytes in a tie-2 and integrin-independent

M. (2004). Vascular endothelial growth factor stimulates skeletal muscle

**5. Conclusions**

**6. Acknowledgements**

97(6): 512-23.

**7. References**

Angiopoietin-1 for Myocardial Angiogenesis 193

Haider H, Ye L, Jiang S, Ge R, Law PK, Chua T, Wong P, Sim EK. Angiomyogenesis for

Haider KH, Kim HW, Ashraf M. (2009). Hypoxia-inducible factor-1alpha in stem cell

Hamaguchi I, Morisada T, Azuma M, Murakami K, Kuramitsu M, Mizukami T, Ohbo K,

Hansen TM, Singh H, Tahir TA, Brindle NP. (2010). Effects of angiopoietins-1 and -2 on the

Harfouche R, Gratton JP, Yancopoulos GD, Noseda M, Karsan A, Hussain SN. (2003).

Hattori K, Dias S, Heissig B, Hackett NR, Lyden D, Tateno M, Hicklin DJ, Zhu Z, Witte L,

Hayes AJ, Huang WQ, Mallah J, Yang D, Lippman ME, Li LY. (1999). Angiopoietin-1 and its

Hiasa K, Ishibashi M, Ohtani K, Inoue S, Zhao Q, Kitamoto S, Sata M, Ichiki T, Takeshita A,

Huang H, & Tindall DJ. (2007). Dynamic FoxO transcription factors. *J Cell Sci* 120(Pt 15):

Huang J, Bae JO, Tsai JP, Kadenhe-Chiweshe A, Papa J, Lee A, Zeng S, Kornfeld ZN, Ullner

Huang J, Zhang Z, Guo J, Ni A, Deb A, Zhang L, Mirotsou M, Pratt RE, Dzau VJ. (2010)

Hughes DP, Marron MB, Brindle NP. (2003). The antiinflammatory endothelial tyrosine

Jeon BH, Khanday F, Deshpande S, Haile A, Ozaki M, Irani K. (2003). Tie-ing the

and hematopoietic stem cells. *J Exp Med* 193(9): 1005-14.

survival of endothelial cells. *Microvasc Res* 58(3): 224-37.

growth factor. *J Mol Med* 82(8): 539-49.

*Cardiovasc Surg* 138(1): 257.

survival. *Blood* 107(3): 1207-13.

surface. *Cell Signal* 22(3): 527-32.

kinases. *Faseb J* 17(11): 1523-5.

2479-87.

*Oncol* 34(1): 79-87.

92(6): 630-6.

586-8.

myocardium. *Circ Res* 106(11): 1753-62.

cardiac repair using human myoblasts as carriers of human vascular endothelial

preconditioning: mechanistic role of hypoxia-related micro-RNAs. *J Thorac*

Yamaguchi K, Oike Y, Dumont DJ, Suda T. (2006). Loss of Tie2 receptor compromises embryonic stem cell-derived endothelial but not hematopoietic cell

receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell

Angiopoietin-1 activates both anti- and proapoptotic mitogen-activated protein

Crystal RG, Moore MA, Rafii S. (2001). Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic

receptor Tie-2 participate in the regulation of capillary-like tubule formation and

Egashira K. (2004). Gene transfer of stromal cell-derived factor-1alpha enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: next-generation chemokine therapy for therapeutic neovascularization. *Circulation* 109(20): 2454-61.

P, Zaghloul N, Ioffe E, Nandor S, Burova E, Holash J, Thurston G, Rudge J, Yancopoulos GD, Yamashiro DJ, Kandel JJ. (2009). Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade. *Int J*

Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured

kinase Tie2 interacts with a novel nuclear factor-kappaB inhibitor ABIN-2. *Circ Res*

antiinflammatory effect of angiopoietin-1 to inhibition of NF-kappaB. *Circ Res* 92(6):

Dumont DJ, Yamaguchi TP, Conlon RA, Rossant J, Breitman ML. (1992). tek, a novel

Eguchi M, Masuda H, Asahara T. (2007). Endothelial progenitor cells for postnatal

Elmadbouh I, Haider H, Jiang S, Idris NM, Lu G, Ashraf M. (2007). Ex vivo delivered

Feng Y, Vom Hagen F, Wang Y, Beck S, Schreiter K, Pfister F, Hoffmann S, Wagner P,

Fiedler U, Krissl T, Koidl S, Weiss C, Koblizek T, Deutsch U, Martiny-Baron G, Marme D,

Fouts K, Fernandes B, Mal N, Liu J, Laurita KR. (2006). Electrophysiological consequence of

Fujii, T. & H. Kuwano Regulation of the expression balance of angiopoietin-1 and angiopoietin-2 by Shh and FGF-2. *In Vitro Cell Dev Biol Anim* 46(6): 487-91. Fujikawa K, de Aos Scherpenseel I, Jain SK, Presman E, Christensen RA, Varticovski L.

Gale NW, Thurston G, Davis S, Wiegand SJ, Holash J, Rudge JS, Yancopoulos GD. (2002).

Gomei Y, Nakamura Y, Yoshihara H, Hosokawa K, Iwasaki H, Suda T, Arai F. (2010)

Gratton JP, Morales-Ruiz M, Kureishi Y, Fulton D, Walsh K, Sessa WC. (2001). Akt down-

Gurunluoglu R, Ozer K, Skugor B, Lubiatowski P, Carnevale K, Siemionow M. (2002). Effect

Haider H, Jiang S, Idris NM, Ashraf M. (2008). IGF-1-overexpressing mesenchymal stem

adenovirus encoding the VEGF gene. *Ann Plast Surg* 49(2): 161-9.

dependent survival of endothelial cells. *Exp Cell Res* 253(2): 663-72.

cells and their presumptive precursors. *Oncogene* 7(8): 1471-80.

vasculogenesis. *Clin Exp Nephrol* 11(1): 18-25.

retinopathy. *Thromb Haemost* 102(1): 120-30.

growth factor-like repeats. *J Biol Chem* 278(3): 1721-7.

factors. *Circ Res* 102(6): 686-94.

*Heart Rhythm* 3(4): 452-61.

267-73.

30359-65.

tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial

stromal cell-derived factor-1alpha promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium. *J Mol Cell Cardiol* 42(4): 792-803. Evans-Anderson HJ, Alfieri CM, Yutzey KE. (2008). Regulation of cardiomyocyte

proliferation and myocardial growth during development by FOXO transcription

Seeliger M, Molema G, Deutsch U, Hammes HP. (2009). The absence of angiopoietin-2 leads to abnormal vascular maturation and persistent proliferative

Augustin HG. (2003). Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal

skeletal myoblast transplantation in normal and infarcted canine myocardium.

(1999). Role of PI 3-kinase in angiopoietin-1-mediated migration and attachment-

Complementary and coordinated roles of the VEGFs and angiopoietins during normal and pathologic vascular formation. *Cold Spring Harb Symp Quant Biol* 67:

Functional differences between two Tie2 ligands, angiopoietin-1 and -2, in regulation of adult bone marrow hematopoietic stem cells." *Exp Hematol* 38(2): 82-9.

regulation of p38 signaling provides a novel mechanism of vascular endothelial growth factor-mediated cytoprotection in endothelial cells. *J Biol Chem* 276(32):

of transfection time on the survival of epigastric skin flaps pretreated with

cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair. *Circ Res* 103(11): 1300-8.

Angiopoietin-1 for Myocardial Angiogenesis 195

Lyons MS, Bell B, Stainier D, Peters KG. (1998). Isolation of zebrafish homologues for the tie-

Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ. (2003).

Matsumoto R, Omura T, Yoshiyama M, Hayashi T, Inamoto S, Koh KR, Ohta K, Izumi Y,

Murray BW, Padrique ES, Pinko C, McTigue MA. (2001). Mechanistic effects of

Niagara MI, Haider H, Ye L, Koh VS, Lim YT, Poh KK, Ge R, Sim EK. (2004). Autologous

Piao W, Wang H, Inoue M, Hasegawa M, Hamada H, Huang J. (2010). Transplantation of

Saharinen P, Kerkela K, Ekman N, Marron M, Brindle N, Lee GM, Augustin H, Koh GY,

Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M,

infarcted myocardium of type 1 diabetic rats. *Diabetes* 59(1): 51-60.

characterization of Tie2 and phospho-Tie2. *Biochemistry* 40(34): 10243-53. Nakayama T, Hatachi G, Wen CY, Yoshizaki A, Yamazumi K, Niino D, Sekine I. (2005).

with clinicopathological factors. *World J Gastroenterol* 11(7): 964-9.

treatment of hind limb ischemia. *J Vasc Surg* 40(4): 774-85.

disease." *Angiogenesis* 13(3): 203-10.

ligands. *Mol Cell* 37(5): 643-55.

acute myocardial infarction. *Arterioscler Thromb Vasc Biol* 25(6): 1168-73. McCarter SD, Lai PF, Suen RS, Stewart DJ. (2006). Regulation of endothelin-1 by Ang-1: implications for inflammation. *Exp Biol Med (Maywood)* 231(6): 985-91. Morris PN, Dunmore BJ, Tadros A, Marchuk DA, Darland DC, D'Amore PA, Brindle NP.

angiogenesis. *Science* 277(5322): 55-60.

performance of infarcted hearts. *Nat Med* 9(9): 1195-201.

causing venous malformations. *J Mol Med* 83(1): 58-63.

1 and tie-2 endothelium-specific receptor tyrosine kinases. *Dev Dyn* 212(1): 133-40. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D,

McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD. (1997). Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo

Mesenchymal stem cells modified with Akt prevent remodeling and restore

Nakamura Y, Akioka K, Kitaura Y, Takeuchi K, Yoshikawa J. (2005). Vascular endothelial growth factor-expressing MSC transplantation for the treatment of

(2005). Functional analysis of a mutant form of the receptor tyrosine kinase Tie2

autophosphorylation on receptor tyrosine kinase catalysis: enzymatic

Expression and significance of Tie-1 and Tie-2 receptors, and angiopoietins-1, 2 and 4 in colorectal adenocarcinoma: Immunohistochemical analysis and correlation

skeletal myoblasts transduced with a new adenoviral bicistronic vector for

sendai viral angiopoietin-1-modified mesenchymal stem cells for ischemic limb

Alitalo K. (2005). Multiple angiopoietin recombinant proteins activate Tie1 receptor tyrosine kinase and promote its interaction with Tie2.*J Cell Biol* 169(2): 239-43. Samuel SM, Akita Y, Paul D, Thirunavukkarasu M, Zhan L, Sudhakaran PR, Li C, Maulik N.

Coadministration of adenoviral vascular endothelial growth factor and angiopoietin-1 enhances vascularization and reduces ventricular remodeling in the

Gridley T, Wolburg H, Risau W, Qin Y. (1995). Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. *Nature* 376(6535): 70-4. Seegar TC, Eller B, Tzvetkova-Robev D, Kolev MV, Henderson SC, Nikolov DB, Barton WA.

(2010). Tie1-Tie2 interactions mediate functional differences between angiopoietin

Jiang S, Haider H, Idris NM, Salim A, Ashraf M. (2006). Supportive interaction between cell

Kanda S, Miyata Y, Mochizuki Y, Matsuyama T, Kanetake H. (2005). Angiopoietin 1 is

Kim HW, Haider HK, Jiang S, Ashraf M. (2009). Ischemic preconditioning augments

Kim I, Oh JL, Ryu YS, So JN, Sessa WC, Walsh K, Koh GY. (2002). Angiopoietin-1 negatively

Kim I, Ryu YS, Kwak HJ, Ahn SY, Oh JL, Yancopoulos GD, Gale NW, Koh GY. (2002). EphB

Kim SK, Pak HN, Park JH, Fang YF, Kim GI, Park YD, Hwang C, Kim YH, Kim BS. Cardiac

Koblizek TI, Weiss C, Yancopoulos GD, Deutsch U, Risau W. (1998). Angiopoietin-1

Kosacka J, Figiel M, Engele J, Hilbig H, Majewski M, Spanel-Borowski K. (2005).

Labovsky V, Hofer EL, Feldman L, Fernandez Vallone V, Garcia Rivello H, Bayes-Genis A,

Lee S, Kim W, Kim DH, Moon SO, Jung YJ, Lee AS, Kang KP, Jang KY, Lee SY, Sung MJ,

Lu G, Haider HK, Jiang S, Ashraf M. (2009). Sca-1+ stem cell survival and engraftment in the

promotes angiomyogenesis for cardiac repair. *Circ Res* 99(7): 776-84. Kalka C, Masuda H, Takahashi T, Gordon R, Tepper O, Gravereaux E, Pieczek A, Iwaguro

mitogenic for cultured endothelial cells. *Cancer Res* 65(15): 6820-7.

bind and phosphorylate Tie2. *J Biol Chem* 280(20): 20126-31.

induces sprouting angiogenesis in vitro. *Curr Biol* 8(9): 529-32.

from neonatal rat cardiomyocytes. *Differentiation* 79(2): 93-101.

through the PI3K/Akt pathway. *Acta Pharmacol Sin* 29(7): 815-22.

positive for Tie-2 receptor. *Cell Tissue Res* 320(1): 11-9.

*Circ Res* 86(12): 1198-202.

126-8.

*Young* 20(3): 308-17.

119(19): 2587-96.

protein 2. *J Biol Chem* 284(48): 33161-8.

survival signaling and angiocompetent factors enhances donor cell survival and

H, Hayashi SI, Isner JM, Asahara T. (2000). Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects.

survival of stem cells via miR-210 expression by targeting caspase-8-associated

regulates expression and activity of tissue factor in endothelial cells. *Faseb J* 16(1):

ligand, ephrinB2, suppresses the VEGF- and angiopoietin 1-induced Ras/mitogenactivated protein kinase pathway in venous endothelial cells. *Faseb J* 16(9): 1126-8. Kim KT, Choi HH, Steinmetz MO, Maco B, Kammerer RA, Ahn SY, Kim HZ, Lee GM, Koh

GY. (2005). Oligomerization and multimerization are critical for angiopoietin-1 to

cell therapy with mesenchymal stem cell induces cardiac nerve sprouting, angiogenesis, and reduced connexin43-positive gap junctions, but concomitant electrical pacing increases connexin43-positive gap junctions in canine heart. *Cardiol*

Angiopoietin-1 promotes neurite outgrowth from dorsal root ganglion cells

Hernando Insua A, Levin MJ, Chasseing NA. (2010). Cardiomyogenic differentiation of human bone marrow mesenchymal cells: Role of cardiac extract

Koh GY, Park SK. (2008). Protective effect of COMP-angiopoietin-1 on cyclosporine-induced renal injury in mice. *Nephrol Dial Transplant* 23(9): 2784-94. Liu XB, Jiang J, Gui C, Hu XY, Xiang MX, Wang JA. (2008). Angiopoietin-1 protects

mesenchymal stem cells against serum deprivation and hypoxia-induced apoptosis

infarcted heart: dual role for preconditioning-induced connexin-43. *Circulation*

Angiopoietin-1 for Myocardial Angiogenesis 197

Thurston, G. (2002). "Complementary actions of VEGF and angiopoietin-1 on blood vessel

Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, McDonald DM,

Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM. (1999).

Tuo QH, Xiong GZ, Zeng H, Yu HD, Sun SW, Ling HY, Zhu BY, Liao DF, Chen JX. (2010).

angiopoietin-2 and high glucose condition. *Acta Pharmacol Sin* 32(1): 45-51. Uemura R, Xu M, Ahmad N, Ashraf M. (2006). BM stem cells prevent left ventricular

Valenzuela DM, Griffiths JA, Rojas J, Aldrich TH, Jones PF, Zhou H, McClain J, Copeland

Voskas D, Jones N, Van Slyke P, Sturk C, Chang W, Haninec A, Babichev YO, Tran J, Master

Wang H, Zhang Y, Toratani S, Okamoto T. (2004). Transformation of vascular endothelial

Wang Y, Haider HK, Ahmad N, Xu M, Ge R, Ashraf M. (2006). Combining pharmacological

Yau TM, Kim C, Li G, Zhang Y, Fazel S, Weisel RD, Li RK. (2007). Enhanced angiogenesis with multimodal cell-based gene therapy. *Ann Thorac Surg* 83(3): 1110-9. Ye L, Haider H, Jiang S, Tan RS, Ge R, Law PK, Sim EK. (2007). Improved angiogenic

Ye L, Haider H, Jiang S, Tan RS, Toh WC, Ge R, Sim EK. (2007). Angiopoietin-1 for

Ye L, Haider H, Tan R, Toh W, Law PK, Tan W, Su L, Zhang W, Ge R, Zhang Y, Lim Y, Sim

Yu Y, Varughese J, Brown LF, Mulliken JB, Bischoff J. (2001). Increased Tie2 expression,

in hemangioma-derived endothelial cells. *Am J Pathol* 159(6): 2271-80.

VEGF is more effective for cardiac repair. *J Mol Cell Cardiol* 40(5): 736-45. Witzenbichler B, Maisonpierre PC, Jones P, Yancopoulos GD, Isner JM. (1998). Chemotactic

mice and humans.  *Am J Pathol* 166(3): 843-55.

haemangioma. *Oncogene* 23(53): 8700-4.

9(5): 458-65.

*Circulation* 116(11 Suppl): I113-20.

tyrosine kinase Tie2. *J Biol Chem* 273(29): 18514-21.

Yancopoulos GD. (2000). Angiopoietin-1 protects the adult vasculature against

Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-

Angiopoietin-1 protects myocardial endothelial cell function blunted by

remodeling of ischemic heart through paracrine signaling." *Circ Res* 98(11): 1414-21.

NG, Gilbert DJ, Jenkins NA, Huang T, Papadopoulos N, Maisonpierre PC, Davis S, Yancopoulos GD. (1999). Angiopoietins 3 and 4: diverging gene counterparts in

Z, Chen S, Ward N, Cruz M, Jones J, Kerbel RS, Jothy S, Dagnino L, Arbiser J, Klement G, Dumont DJ. (2005). A cyclosporine-sensitive psoriasis-like disease

cells by a point mutation in the Tie2 gene from human intramuscular

mobilization with intramyocardial delivery of bone marrow cells over-expressing

properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor

response in pig heart following ischaemic injury using human skeletal myoblast simultaneously expressing VEGF165 and angiopoietin-1. *Eur J Heart Fail* 9(1): 15-22.

myocardial angiogenesis: a comparison between delivery strategies. *Eur J Heart Fail*

EK. (2007). Transplantation of nanoparticle transfected skeletal myoblasts overexpressing vascular endothelial growth factor-165 for cardiac repair.

enhanced response to angiopoietin-1, and dysregulated angiopoietin-2 expression

growth and leakage. *J Ana*t 200(6): 575-80.

plasma leakage. *Nat Med* 6(4): 460-3.

1. *Science* 286(5449): 2511-4.

Shujia J, Haider HK, Idris NM, Lu G, Ashraf M. (2008). Stable therapeutic effects of

Shyu KG, Chang H, Isner JM. (2003). Synergistic effect of angiopoietin-1 and vascular

Siddiqui AJ, Blomberg P, Wardell E, Hellgren I, Eskandarpour M, Islam KB, Sylven C.

Sundberg C, Kowanetz M, Brown LF, Detmar M, Dvorak HF. (2002). Stable expression of

Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos

Suri C, McClain J, Thurston G, McDonald DM, Zhou H, Oldmixon EH, Sato TN,

Suzuki K, Murtuza B, Smolenski RT, Sammut IA, Suzuki N, Kaneda Y, Yacoub MH. (2001).

Takahara K, Iioka T, Furukawa K, Uchida T, Nakashima M, Tsukazaki T, Shindo H. (2004).

Tang J, Wang J, Guo L, Kong X, Yang J, Zheng F, Zhang L, Huang Y. (2010). Mesenchymal

Tang YL, Zhao Q, Zhang YC, Cheng L, Liu M, Shi J, Yang YZ, Pan C, Ge J, Phillips MI.

Thomas M, Augustin HG. (2009). The role of the Angiopoietins in vascular morphogenesis.

neovascularization in ischemic myocardium. *Regul Pept* 117(1): 3-10. Tao Z, Chen B, Tan X, Zhao Y, Wang L, Zhu T, Cao K, Yang Z, Kan YW, Su H.

the ischemic myocardium. *Biochem Biophys Res Commun* 310(3): 1002-9. Song H, Suehiro J, Kanki Y, Kawai Y, Inoue K, Daida H, Yano K, Ohhashi T, Oettgen P, Aird

with acute hindlimb ischemia. *Life Sci* 73(5): 563-79.

*Res* 77(3): 525-33.

vivo. *Lab Invest* 82(4): 387-401.

embryonic angiogenesis. *Cell* 87(7): 1171-80.

angiopoietin-1. *Science* 282(5388): 468-71.

arthritis. *Hum Pathol* 35(2): 150-8.

*Angiogenesis* 12(2): 125-37.

myocardial infarction." *Mol Cells* 29(1): 9-19.

(MI) heart. *Proc Natl Acad Sci U S A* 108(5): 2064-9.

24.

1): I207-12.

mesenchymal stem cell-based multiple gene delivery for cardiac repair. *Cardiovasc*

endothelial growth factor on neoangiogenesis in hypercholesterolemic rabbit model

(2003). Combination of Ang-1 and VEGF gene therapy enhances arteriogenesis in

WC, Kodama T, Minami T. (2009). Critical role for GATA3 in mediating Tie2 expression and function in large vessel endothelial cells. *J Biol Chem* 284(42): 29109-

angiopoietin-1 and other markers by cultured pericytes: phenotypic similarities to a subpopulation of cells in maturing vessels during later stages of angiogenesis in

GD. (1996). Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during

Yancopoulos GD. (1998). Increased vascularization in mice overexpressing

Cell transplantation for the treatment of acute myocardial infarction using vascular endothelial growth factor-expressing skeletal myoblasts. *Circulation* 104(12 Suppl

Autocrine/paracrine role of the angiopoietin-1 and -2/Tie2 system in cell proliferation and chemotaxis of cultured fibroblastic synoviocytes in rheumatoid

stem cells modified with stromal cell-derived factor 1 alpha improve cardiac remodeling via paracrine activation of hepatocyte growth factor in a rat model of

(2004). Autologous mesenchymal stem cell transplantation induce VEGF and

Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction

**Part 2**

**Pathogenesis of Myocarditis**