Angiogenesis Center


The Angiogenesis Center represents a comprehensive research program designed to discover and understand the basic mechanisms underlying blood vessel formation in the settings of tumor progression and ischemic diseases. Angiogenic therapy represents a new direction in the treatment for cancer, peripheral vascular and heart disease and it is crucial to continue research efforts focused on the development of new strategies targeting neovasculature.

The Angiogenesis Center at the Cleveland Clinic bridges basic researchers within theLerner Research Institute and clinical investigators within several other Cleveland Clinic Institutes involved in the development and clinical evaluations of anti- as well as pro-angiogenic drugs. The center combines the expertise of investigators with interests in the mechanisms of tumor vascularization, the development of novel anti-angiogenic strategies in age-related macular degeneration, and the efforts of cardiovascular biologists.

Vascular Functions In Vitro and Ex Vivo

Primary endothelial cell isolation (Anand-Apte, Byzova, McCrae)

Endothelial cell proliferation and migration assays (Anand-Apte, Byzova, Gladson, McCrae, Schmaier)

Sprouting and cord formation angiogenesis assays (Byzova, Schmaier)

Tubulomorphogenesis assays (Gladson)

Dunn chamber chemotaxis (Horowitz)

Embryoid body vascular differentiation (Horowitz)

Mouse blastocyst isolation and ES culture (Horowitz)

Trachea venule extravasation (Horowitz)

Matrigel plug assays (Byzova, McCrae, Schmaier)

Eye Vasculature Assays

Corneal micropocket assay (Anand-Apte)

Intra-vitreal injections (Anand-Apte)

Retinal and choroidal vascular development (Anand-Apte)

Retinopathy of Prematurity model (Anand-Apte)

Retinal vasculature isolation and immunofluorescence (Horowitz)

Tumor Models in Vasculature

Angiogenesis in the wound (Byzova)

Assessment of microvessel density in tumor xenografts (Byzova,

Gladson, McCrae)

Intracerebral injection of tumor cells (Gladson)

Cardiovascular Models

Model of myocardial ischemia/reperfusion injury in angiogenesis (Byzova)

Micro CT analysis of vasculature (Byzova)

Pluskota E, Dowling JJ, Gordon N, Golden JA, Szpak D, West XZ, Nestor C, Ma YQ, Bialkowska K, Byzova T, Plow EF. The integrin co-activator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish. Blood. 2011 Mar 4. [Epub ahead of print]

Feng, W, Madajka M, Kerr BA, Mahabeleshwar GH, Whiteheart SW, Byzova TV. “A novel role for platelet secretion in angiogenesis: Mediating bone marrow-derived cell mobilization and homing.” Blood. 2011 Mar 2. [Epub ahead of print]

Yang K, Proweller A. Vascular smooth muscle notch signals regulate endothelial cell sensitivity to angiogenic stimulation.  J Biol Chem. 2011 Feb 23. [Epub ahead of print]

Ebrahem Q, Qi JH, Sugimoto M, Ali M, Sears J, Cutler A, Khokha R, Vasanji A, Anand-Apte B.  Increased neovascularization in mice lacking tissue inhibitor of metalloproteinases-3. Invest Ophthalmol Vis Sci. 2011 Jan 31. [Epub ahead of print]

Rahaman SO, Swat W, Febbraio M, Silverstein RL.  Vav Family Rho Guanine Nucleotide Exchange Factors Regulate CD36-mediated Macrophage Foam Cell Formation.  J Biol Chem. 2011 Mar 4;286(9):7010-7.

Nieman MT, LaRusch G, Fang C, Zhou Y, Schmaier AH. Oral thrombostatin FM19 inhibits prostate cancer. Thromb Haemost. 2010 Nov 3;104(5):1044-8.

West XZ, Malinin NL, Merkulova AA, Tischenko M, Kerr BA, Borden EC, Podrez EA, Salomon RG, Byzova TV. “Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands.” Nature. 2010 Oct 21;467(7318):972-6.

LaRusch GA, Mahdi F, Shariat-Madar Z, Adams G, Sitrin RG, Zhang WM, McCrae KR, Schmaier AH. Factor XII stimulates ERK1/2 and Akt through uPAR, integrins, and the EGFR to initiate angiogenesis. Blood. 2010 Jun 17;115(24):5111-20.

Han Y, Kuang SZ, Gomer A, Ramirez-Bergeron DL. Hypoxia influences the vascular expansion and differentiation of embryonic stem cell cultures through the temporal expression of vascular endothelial growth factor receptors in an ARNT-dependent manner. Stem Cells. 2010 Apr;28(4):799-809.

Klenotic PA, Huang P, Palomo J, Kaur B, Van Meir EG, Vogelbaum MA, Febbraio M, Gladson CL, Silverstein RL.  Histidine-rich glycoprotein modulates the anti-angiogenic effects of vasculostatin. Am J Pathol. 2010 Apr;176(4):2039-50.

Koo BH, Coe DM, Dixon LJ, Somerville RP, Nelson CM, Wang LW, Young ME, Lindner DJ, Apte SS. ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells. Am J Pathol. 2010 Mar;176(3):1494-504.

Ebrahem Q, Chaurasia SS, Vasanji A, Qi JH, Klenotic PA, Cutler A, Asosingh K, Erzurum S, Anand-Apte B. Cross-talk between vascular endothelial growth factor and matrix metalloproteinases in the induction of neovascularization in vivo. Am J Pathol. 2010 Jan;176(1):496-503.

Heddleston JM, Li Z, McLendon RE, Hjelmeland AB, Rich JN. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle. 2009 Oct 15;8(20):3274-84.

Kawanami D, Mahabeleshwar GH, Lin Z, Atkins GB, Hamik A, Haldar SM, Maemura K, Lamanna JC, Jain MK.  Kruppel-like factor 2 inhibits hypoxia-inducible factor 1alpha expression and function in the endothelium. J Biol Chem. 2009 Jul 31;284(31):20522-30.

Qi JH, Dai G, Luthert P, Chaurasia S, Hollyfield J, Weber BH, Stöhr H, Anand-Apte B. S156C mutation in tissue inhibitor of metalloproteinases-3 induces increased angiogenesis. J Biol Chem. 2009 Jul 24;284(30):19927-36.

Wikenheiser J, Wolfram JA, Gargesha M, Yang K, Karunamuni G, Wilson DL, Semenza GL, Agani F, Fisher SA, Ward N, Watanabe M. Altered hypoxia-inducible factor-1 alpha expression levels correlate with coronary vessel anomalies. Dev Dyn. 2009 Oct;238(10):2688-700.

Fan C, Ouyang P, Timur AA, He P, You SA, Hu Y, Ke T, Driscoll DJ, Chen Q, Wang QK. Novel roles of GATA1 in regulation of angiogenic factor AGGF1 and endothelial cell function. J Biol Chem. 2009 Aug 28;284(35):23331-43.

McFarland BC, Stewart J Jr, Hamza A, Nordal R, Davidson DJ, Henkin J, Gladson CL. Plasminogen kringle 5 induces apoptosis of brain microvessel endothelial cells: sensitization by radiation and requirement for GRP78 and LRP1. Cancer Res. 2009 Jul 1;69(13):5537-45.

The Annual Angiogenesis Center Outstanding Manuscript Award

Each year, the Angiogenesis Center recognizes a Cleveland Clinic researcher for his or her outstanding contribution to research in the field of Angiogenesis and Vascular Biology. Manuscripts with key topics such as “endothelial,” “vascular,” and “angiogenesis,” and with a publication date falling between January 1 of the previous year and June 30 of the award year, are eligible. Scoring for each manuscript is determined by a combination of its number of citations and the publishing journal’s impact factor.

Previous winners of this prestigious award are:

2014: Lin Cheng, PhD, Department of Stem Cell Biology and Regenerative Medicine

Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth

Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, Fang X, Sloan AE, Mao Y, Lathia JD, Min W, McLendon RE, Rich JN, Bao S

Cell. 2013 Mar 28;153(1):139-52. doi: 10.1016/j.cell.2013.02.021.


2013: Yi Fan, MD, PhD, Department of Cellular and Molecular Medicine

Stimulus-dependent phosphorylation of profilin-1 in angiogenesis

Fan Y, Arif A, Gong Y, Jia J, Eswarappa SM, Willard B, Horowitz A, Graham LM, Penn MS, Fox PL

Nat Cell Biol. 2012 Oct;14(10):1046-56. doi: 10.1038/ncb2580.

After working as a Research Scientist at the Clinic, Dr. Fan gained employment as Assistant Professor of Radiation Oncology at University of Pennsylvania’s Perelman School of Medicine.


2012: Brian Rini, MD, Department of Hematology and Oncology

Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial

Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ

Lancet. 2011 Dec 3;378(9807):1931-9. doi: 10.1016/S0140-6736(11)61613-9.

Dr. Rini is a Staff member at the Clinic’s Taussig Cancer Center in the Department of Solid Tumor Oncology, where his work is focused on genitourinary malignancies.

Tatiana Byzova, Ph.D., FAHA

Director of Angiogenesis Center

(216) 445-4312


Lisa Plungas

Department Coordinator

(216) 445-8209