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Genetic heterogeneity of angiogenesis in mice

Division of Surgical Research, Children’s Hospital, Boston, Massachusetts 02115, USA; and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02115, USA

¹Correspondence: Children’s Hospital, Enders 1006, 300 Longwood Ave., Boston, MA 02115, USA. E-mail: damato_r{at}a1.tch.harvard.edu

	ABSTRACT

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Many diseases, including cancer, are dependent on the growth of new blood vessels, a process known as angiogenesis. Differences in an individual’s ability to grow new blood vessels may influence the rate of progression of these diseases. Here we show that different strains of inbred mice have an ~10-fold range of response to growth factor-stimulated angiogenesis in the corneal micropocket assay. The in vitro migratory activity of endothelial cells from aortic rings of selected strains correlated with the in vivo responsiveness. Further, a differential sensitivity to angiogenesis inhibitors was seen between strains, with one strain demonstrating resistance to both TNP-470 and thalidomide. These results suggest the presence of genetic factors that control individual angiogenic potential.—Rohan, R. M., Fernandez, A., Udagawa, T., Yuan, J., D’Amato, R. J. Genetic heterogeneity of angiogenesis in mice.

Key Words: growth factors • blood vessels • endothelial cells • inbred strains

	INTRODUCTION

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ANGIOGENESIS NORMALLY OCCURS in the female reproductive system (1) , in fetal development (2) , and in wound healing (3) as well as in pathological states such as solid tumor growth (4 5 6) , hemangiomas (7) , and retinopathies (8) . With the exception of these conditions, vascular endothelial cells rarely proliferate and instead remain differentiated and quiescent (9) . This quiescence is the result of low levels of endothelial growth stimulators and high basal levels of inhibitors such as thrombospondin and transforming growth factor ß (10) . In pathological conditions, such as diabetic retinopathy, angiogenesis is promoted by increasing levels of stimulators such as vascular endothelial cell growth factor (VEGF) (11) . Thus, the stimulator to inhibitor ratio regulates the degree of angiogenesis. To determine whether this angiogenic balance was genetically determined, we measured the sensitivity of different inbred strains of mice to angiogenic growth factors using a corneal neovascularization model (12 , 13) .

	MATERIALS AND METHODS

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Cornea micropocket assay
After animals were anesthetized, corneal micropockets were created in both eyes with a modified von Graefe cataract knife. Into each pocket, a 0.4 mm x 0.4 mm x 0.2 mm sucrose aluminum sulfate pellet coated with hydron polymer type NCC (Interferon Sciences, New Brunswick, N.J.) containing 10–80 ng of basic fibroblast growth factor (bFGF) was implanted 1.0–1.2 mm from the limbal vessels. For VEGF experiments, pellets containing 160 ng of human recombinant VEGF were implanted 0.5–0.7 mm from the limbus. These pellets are extremely uniform because they are formed with a nylon mesh of 0.4 mm pore size that serves as a mold. The sucrose aluminum sulfate (also known as sucralfate; Bukh Meditec, Copenhagen, Denmark) acts to stabilize the growth factors and slow its release from the hydron. Erythromycin ointment was applied to each operated eye postoperatively. The induced vascular response (measured as the maximal vessel length and number of clock hours of neovascularization) was assessed on the fifth postoperative day (or sixth postoperative day for VEGF). The area was calculated as described previously (13) . In all experiments, each eye was treated as an independent measurement and the data are reported as the mean ± standard deviation.

All mice were assayed at 7–9 wk of age. The ages were matched to eliminate potential influences of age-induced changes in corneal shape (even though our previous experience has found a constant amount of induced angiogenesis in the corneas of mice from ages 8 wk to 60 wk old). Thalidomide and TNP-470 were gifts of EntreMed and TAP Pharmaceuticals, respectively.

Aortic ring assay
Briefly, 150 µl of matrigel (Collaborative Biomedical Products, Bedford, Mass.) was used per well to create the basal layer in a 48-well plate. An aortic section (~1 mm long) taken from 129/ReJ, C57BL/6J, or SJL/J mice was placed on its side on top of this layer and immediately covered with 150 µl of matrigel. The matrigel overlay was allowed to gel for 6 h, then incubated for 5 days without or with serum free EBM-2 media supplemented with a combination of growth factors optimized for endothelial cell growth (Singlequotes from Clonetics, San Diego, Calif.). On day 5, sprouts were counted under the microscope and the endothelial nature of the cells in the sprouts was confirmed by their ability to incorporate fluorescent labeled acetylated LDL (Biomedical Technologies Inc., Stoughton, Mass.).

	RESULTS

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Uniform-sized hydron pellets containing growth factors were implanted into the corneal stroma of different inbred strains of mice. In C57BL/6J mice, a nearly maximal response without substantial inflammation was obtained with pellets containing 80 ng of bFGF (12) . This dose was selected to delineate strains with reduced angiogenesis relative to the C57BL/6J strain. Three strains (FVB, ICR, and SJL/J) had a significantly lower angiogenic response (Table 1 and Fig. 1 ). Conversely, submaximal doses of 10 ng bFGF were used to detect strains with enhanced angiogenesis. Several strains (including all of the 129 substrains, C58, P, PL, and SWR) had an increase in neovascularization relative to C57BL/6J at this dose. One of the 129 substrains, 129/SvImJ, had a higher response than any of the other strains tested.

View larger version (93K): [in this window] [in a new window]   Figure 1. Corneal neovascular response in different inbred mouse strains. Typical neovascular response of different inbred mouse strains 5 days after implantation of corneal pellets containing 10 ng or 80 ng bFGF. (Arrows label the tips of the vessels in the advancing neovascular front. The growth factor pellet is identified by ‘P’.) Top panel: Minimal neovascularization is induced by 10 ng bFGF in C57BL/6J mice, in contrast to 129/SvImJ mice, which exhibit an aggressive response. Bottom panel: Higher dose 80 ng bFGF pellets were used to induce a maximal response in the C57BL/6J mice and thus expose the difference between C57BL/6J and SJL/J mice.

The induced neovascular area in C57BL/6J mice was linearly related to the amount of bFGF (5 ng - 80 ng) in the pellet (Fig. 2 ). The induced neovascular area in SJL/J animals, however, reached a plateau at 10 ng bFGF. Analysis of the growth rate of the induced vessels at different doses revealed that the C57BL/6J growth rate increased up to a maximum of 0.25 mm/day at 80 ng pellets whereas the SJL/J mice plateaued at ~0.15 mm/day for doses above 10 ng. 129/SvImJ mice had a similar bFGF dose response as the SJL/J mice albeit with a higher amount of neovascularization and a maximum growth rate of 0.25 mm/day for doses over 10 ng. Analysis of the induced neovascular area vs. the dose of bFGF revealed that the amount of bFGF required to produce a 1.5 mm² neovascular area was ~50 ng, 20 ng, 7.5 ng, and 5 ng for C57BL/6J, 129/J, 129/ReJ, and 129/SvImJ, respectively(data not shown). Thus, there is a 10-fold range in sensitivity to bFGF between C57BL/6J and 129/SvImJ. The differences between the 129 substrains were not surprising given the recent report that outcrossing of the 129 substrains has lead to extensive genetic variability among these substrains (14) .

View larger version (24K): [in this window] [in a new window]   Figure 2. Dose response curve to bFGF with C57BL/6J, SJL/J, and 129/SvImJ mice. 129/SvImJ () respond aggressively to low amounts of bFGF, followed by a plateau over 10 ng producing a near maximal response of 2.8 mm2. C57BL/6J mice have a linear response, with near maximal response at 80 ng of 2.4 mm2. SJL/J (•) mice have an aggressive initial response phase to low doses of bFGF but plateau early, with a maximal induced neovascular area of 1 mm2.

While performing the above dose response experiments, we noted that the albino 129 substrains (129/ReJ and 129/J) had frequent formation of hyphemas (bleeding inside the anterior chamber) with higher dose pellets, which was not seen in the pigmented 129 substrain 129/SvImJ. Indeed, there was a correlation between frequent hyphema formation and lack of pigmentation of the iris (due to either the Tyr-C or pink-eyed dilute alleles) in strains of mice that had an angiogenic phenotype statistically higher than C57BL/6J. Hyphemas were commonly seen in 6/8 nonpigmented strains vs. 1/6 pigmented strains. Slit lamp examination of albino or hypopigmented mice prior to hyphema formation revealed neovascularization on the surface of the iris (data not shown). These new iris vessels are typically friable and bleed easily. Iris neovascularization was not seen in pigmented C57BL/6J mice. To directly determine the influence of iris pigmentation, we examined C57BL/6J-Tyr^c-2J mice that were albino relatives of the reference C57BL/6J line. Implantation of corneal pellets of 80 ng bFGF resulted in hyphema formation in 5 out of 9 eyes of C57BL/6J-Tyr^c-2J as compared to 0 out of 70 eyes of control C57BL/6J mice. As expected, the amount of corneal neovascularization was not significantly different between these two strains, since the cornea is not a pigmented tissue. Similarly, hyphemas were observed in 8 out of 8 eyes of albino 129/Sv mice, but in only 1 out of 19 eyes of the related pigmented strain (+p/+Tyr) known as 129/SvImJ mice (despite the higher corneal angiogenic response in the 129/SvImJ). These data suggest that factors linked to pigmentation/melanin were producing an inhibitory influence on the angiogenic balance in the iris.

The difference in sensitivity between the 129 and C57BL/6J strains was also found with VEGF-induced corneal neovascularization. VEGF pellets (160 ng) stimulated 0.7 ± 0.1 mm² of neovascular area in C57BL/6J mice (n=8) compared to 1.1 ± 0.1 mm² and 1.3 ± 0.1 mm² for 129/J (n=4, P<0.05) and 129/ReJ (n=6, P<0.05), respectively. The fact that the differential angiogenic response is seen with multiple growth factors reinforces the idea that the strain differences are due to a generalized shift in the angiogenic responsiveness. The angiogenic profile does not appear to be influenced by putative differences in the immune system, since we have previously demonstrated a lack of inflammation in this model and have shown that the angiogenic response in severe combined immune deficient mice is similar to other mice (12) .

To determine the sensitivity of different strains to angiogenesis inhibitors, we compared the effect of TNP-470 or thalidomide on 129/ReJ, C57BL/6J, and SJL/J mice. Pellets of varying concentrations of bFGF (5 ng for 129/ReJ, 40 ng for C57BL/6J, and 10 ng for SJL/J) were implanted in order to induce the same amount of neovascularization (~1 mm²) in each strain. These concentrations were on the linear portion of the bFGF dose response curves for each strain so that any inhibitory effect of the inhibitor could be readily detected. Treatment of 129/ReJ, C57BL/6J, and SJL/J with TNP-470 (30 mg/kg q.o.d. S.C.) resulted in 65 ± 11%, 44 ± 9%, and 5 ± 11% inhibition of neovascularization [for 129/ReJ n=17 treated compared to n=16 untreated controls (P<0.001); for C57BL/6J n=10 treated compared to n=9 untreated C57BL/6J controls, (P<0.001); for SJL/J n=8 treated compared to n=10 untreated SJL/J controls (not statistically different)]. The enhanced level of inhibition in 129/ReJ and the lack of inhibition in SJL/J mice were both significantly different from treated C57BL/6J (P<0.001). Treatment of 129/ReJ, C57BL/6J, and SJL/J with thalidomide (200 mg/kg q.d. I.P.) resulted in 18 ± 12%, 29 ± 15%, and 5 ± 11% inhibition of neovascularization [for 129/REJ n=9 treated compared to n=8 untreated controls (P=0.03); for C57BL/6J n=9 treated compared to n=10 untreated C57BL/6J controls, (P<0.0001); for SJL/J n=9 treated compared to n=10 untreated SJL/J controls (not statisitically different)]. Again, the inhibition seen in the C57BL/6J strain was significantly different from the lack of inhibition in SJL/J mice (P<0.01)). Thus we conclude that the genetic background of a particular inbred strain can significantly alter the sensitivity to angiogenesis inhibitors. Indeed, the resistance of SJL/J mice to angiogenesis inhibitors and to maximal stimulation with bFGF suggests a common alteration in endothelial function.

To begin to characterize the inheritance pattern, we examined hybrid animals between the high angiogenic strain, 129/J, and the reference strain, C57BL/6J. These hybrids had a heightened neovascular response similar to the parental 129 strains (see C57BL/6J-A^W-J x 129/J in Table 1 ). In contrast, hybrid animals between the low angiogenic strain SJL/J and the reference strain C57BL/6J are phenotypically closer to the C57BL/6J parental strain (see C57BL/6J x SJL/J in Table 1 ). These data suggest that angiogenic potential is genetically determined and that the higher angiogenic response seen in 129J mice is phenotypically dominant. Examination of F2 generations suggests a multigenic contribution. We have begun to map the genetic loci that control angiogenic potential in these strains. We are also mapping the 129/ReJ substrain due to the high angiogenic response in vivo and its longstanding history as a pure inbred strain (the 129/Sv substrains were excluded because of a history of some genetic contamination) (14) .

To determine whether these strain-related differences in angiogenic sensitivity could be examined in vitro, we compared endothelial outgrowth from aortic rings taken from 129/ReJ, C57BL/6J, and SJL/J mice (Fig. 3 ). Using a modified method of Nicosia (15) , we quantified the number of tubes seen after 5 days in culture either with or without media containing endothelial growth supplement (from Clonetics containing bFGF and VEGF). Tube outgrowth without added growth factors was significantly greater for aortic rings from 129/ReJ mice than C57BL/6J or SJL/J mice. When media supplemented with growth factors was added to the 129/ReJ and C57BL/6J aortic rings, outgrowth was stimulated three- to fourfold, and there was no difference between these strains. However, the SJL/J rings showed little stimulation and had significantly fewer sprouts than the C57BL/6J rings. These results directly correlate with our 10 ng and 80 ng in vivo data, where differences between 129/ReJ and C57BL/6J mice are apparent at low levels of growth factor and differences between C57BL/6J and SJL/J were evident at higher levels of growth factor (due to the SJL/J’s resistance to stimulation). The in vitro correlation implies that strain differences in neovascularization may reflect differences in the endothelial cells themselves.

View larger version (24K): [in this window] [in a new window]   Figure 3. Number of sprouts growing from aortic rings after 5 days with or without added media supplemented with growth factors. Despite the generally low number of sprouts without supplemented media/growth factors, the aortic rings from 129 REJ mice have significantly more sprouts than either C57BL/6J or SJL/J (P=0.001, n=18 per group). The addition of media/growth factors causes a marked increase in sprouting from both the C57BL/6J and 129/SvImJ but not the SJL/J mice, similar to the blunted response seen in the eye assay. The number of sprouts from SJL/J mice was significantly less than either C57BL/6J or 129/SvImJ mice (P=0.0001, n=25 per group).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
These experiments demonstrate the presence of genetic heterogeneity that influences angiogenesis. This heterogeneity may correlate with the resistance of certain strains to tumor growth. For example, FVB mice, which have a significantly lower angiogenic response than C57BL/6J, have also been reported to be more resistant to retinoblastoma growth (16) . Differences in angiogenesis between C57BL/6J and C3H mice have been reported after chronic mycoplasma-induced inflammation; however, this effect was attributed to qualitative differences in the immune response (17) . Our data support this conclusion since no significant difference was detected between these strains when the angiogenesis was directly induced by bFGF (Table 1) .

An understanding of the genetic heterogeneity of angiogenesis responsiveness is essential when studying animal models of angiogenesis. For example, knockouts are commonly made in 129 mice, a strain that is a high angiogenesis responder. This background may complicate the analysis of phenotypes dependent on angiogenesis. We also found differences between 129 substrains, suggesting that there may be differences in knockouts made in different ES cell lines (14) . Furthermore, mice that are low angiogenesis responders may be resistant to certain angiogenesis inhibitors and thus be inadequate for screening of these compounds.

The angiogenic heterogeneity present among inbred mouse strains may implicate a similar heterogeneity present in humans that could correlate with familial susceptibility to disorders dependent on angiogenic activity such as cancer, arthritis, and age-related macular degeneration. Indeed, the inhibitory effect of pigmentation on angiogenesis, as one of the genetically controlled differences between the inbred strains of mice, may have a direct clinical correlation. Caucasians and African-Americans have a similar prevalence of early age-related macular degeneration. However, the progression to the late form of this disease, which is characterized by proliferation of new vessels in the pigmented layer of the eye (known as the choroid), is very rare for African-Americans (18) . Similarly, infantile hemangiomas of the skin are commonly seen in Caucasians but are rare in African-Americans (19) .

We have begun genetic studies to identify genes responsible for the angiogenic phenotypes we observed in inbred murine strains. The characterization of the genes that contribute to the angiogenic phenotypes of mice will lead to the discovery of similar genes in humans. Understanding the role of genetic factors in the regulation of angiogenesis may help predict the clinical outcome of patients with disorders dependent on angiogenesis and assist in identifying those individuals that will be most sensitive to angiogenesis inhibitors in future clinical trials.

	ACKNOWLEDGMENTS

 
This work was supported in part by a research grant from EntreMed Inc.

	FOOTNOTES

 
Received for publication September 7, 1999. Revised for publication November 10, 1999.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

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				C. K. Chan, L. N. Pham, C. Chinn, C. Spee, S. J. Ryan, R. J. Akhurst, and D. R. Hinton Mouse Strain-Dependent Heterogeneity of Resting Limbal Vasculature Invest. Ophthalmol. Vis. Sci., February 1, 2004; 45(2): 441 - 447. [Abstract] [Full Text] [PDF]

				Q. Liu, A. Lyubarsky, J. H. Skalet, E. N. Pugh Jr, and E. A. Pierce RP1 Is Required for the Correct Stacking of Outer Segment Discs Invest. Ophthalmol. Vis. Sci., October 1, 2003; 44(10): 4171 - 4183. [Abstract] [Full Text] [PDF]

				H. Zheng, C. Wasylyk, A. Ayadi, J. Abecassis, J. A Schalken, H. Rogatsch, N. Wernert, S.-M. Maira, M.-C. Multon, and B. Wasylyk The transcription factor Net regulates the angiogenic switch Genes & Dev., September 15, 2003; 17(18): 2283 - 2297. [Abstract] [Full Text] [PDF]

				E. Sakurai, H. Taguchi, A. Anand, B. K. Ambati, E. S. Gragoudas, J. W. Miller, A. P. Adamis, and J. Ambati Targeted Disruption of the CD18 or ICAM-1 Gene Inhibits Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2743 - 2749. [Abstract] [Full Text] [PDF]

				S. Nakao, T. Kuwano, T. Ishibashi, M. Kuwano, and M. Ono Synergistic Effect of TNF-{alpha} in Soluble VCAM-1-Induced Angiogenesis Through {alpha}4 Integrins J. Immunol., June 1, 2003; 170(11): 5704 - 5711. [Abstract] [Full Text] [PDF]

				R. R. White, S. Shan, C. P. Rusconi, G. Shetty, M. W. Dewhirst, C. D. Kontos, and B. A. Sullenger Inhibition of rat corneal angiogenesis by a nuclease-resistant RNA aptamer specific for angiopoietin-2 PNAS, April 29, 2003; 100(9): 5028 - 5033. [Abstract] [Full Text] [PDF]

				S. S. Gerety and D. J. Anderson Cardiovascular ephrinB2 function is essential for embryonic angiogenesis Development, March 5, 2003; 129(6): 1397 - 1410. [Abstract] [Full Text] [PDF]

				K. D. Miller, C. J. Sweeney, and G. W. Sledge The Snark is a Boojum: the continuing problem of drug resistance in the antiangiogenic era Ann. Onc., January 1, 2003; 14(1): 20 - 28. [Abstract] [Full Text] [PDF]

				M. A. Rupnick, D. Panigrahy, C.-Y. Zhang, S. M. Dallabrida, B. B. Lowell, R. Langer, and M. J. Folkman From the Cover: Adipose tissue mass can be regulated through the vasculature PNAS, August 6, 2002; 99(16): 10730 - 10735. [Abstract] [Full Text] [PDF]

				C. J. Sullivan and J. B. Hoying Flow-Dependent Remodeling in the Carotid Artery of Fibroblast Growth Factor-2 Knockout Mice Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1100 - 1105. [Abstract] [Full Text] [PDF]

				A. M. Davidoff, A. C. Nathwani, W. W. Spurbeck, C. Y. C. Ng, J. Zhou, and E. F. Vanin rAAV-mediated Long-term Liver-generated Expression of an Angiogenesis Inhibitor Can Restrict Renal Tumor Growth in Mice Cancer Res., June 1, 2002; 62(11): 3077 - 3083. [Abstract] [Full Text] [PDF]

				Y. Ando, E. Fuse, and W. D. Figg Thalidomide Metabolism by the CYP2C Subfamily Clin. Cancer Res., June 1, 2002; 8(6): 1964 - 1973. [Abstract] [Full Text] [PDF]

				N. B. Haider, A. Ikeda, J. K. Naggert, and P. M. Nishina Genetic modifiers of vision and hearing Hum. Mol. Genet., May 15, 2002; 11(10): 1195 - 1206. [Abstract] [Full Text] [PDF]

				J. Rak, J. L. Yu, R. S. Kerbel, and B. L. Coomber What Do Oncogenic Mutations Have To Do with Angiogenesis/Vascular Dependence of Tumors? Cancer Res., April 1, 2002; 62(7): 1931 - 1934. [Full Text] [PDF]