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Neovascularization in Benign and Malignant Urinary Bladder Epithelial Proliferative Lesions of the Rat Observed in Situ by Scanning Electron Microscopy and Autoradiography¹

First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan

Vascular changes during carcinogenesis and during reversible regenerative hyperplasia of the rat urinary bladder were studied in situ by scanning electron microscopy of vascular casts and by autoradiography of the bladder. Carcinomas were induced in male Wistar rats by administration of 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine in the drinking water for 8 weeks; rats were observed for a total of 40 weeks. Regenerative hyperplasia was produced in male Wistar rats by ulceration with a frozen steel rod; rats were observed for 15 days. It was produced in male Fischer rats by a single injection of cyclophosphamide (200 mg/kg body weight); rats were observed for 21 days.

The subepithelial capillaries of the bladder were arranged as a loose plexus of vessels of relatively uniform diameter, of low density, and connected to larger vessels in the deeper layers. Type 1 vascular proliferations, consisting of a high-density plexus of narrow capillaries with short terminal branches, were first observed at 2 weeks during N-butyl-N-(4-hydroxybutyl)nitrosamine carcinogenesis, increased in number through Week 8, and then decreased. Histologically, hyperplasia was present after 2 weeks, but there was no correlation between epithelial hyperplasia and vascular proliferation. Type 2 foci, larger-diameter vessels with long terminal branches, were observed only during Weeks 7 and 8. Type 3 foci, highly tortuous capillary loops, appeared after 6 weeks and were present with foci of papillary and nodular hyperplasia, papilloma, and cancer.

After ulceration or cyclophosphamide treatment, type 1 foci were observed in areas of granulation tissue and repair in the bladders, and type 3 foci were observed with lesions of papillary and nodular hyperplasia of the epithelium. The epithelial hyperplasia and foci of vascular proliferation were reversible so that the bladders appeared normal by 2 to 3 weeks. Thus, the formation and the reversibility or irreversibility of the type 3 vascular proliferations depend on the extent and reversibility or irreversibility of the epithelial proliferations.

¹ Supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science and Culture of Japan (1977); the Ministry of Health and Welfare of Japan (1977); Society for Promotion of Cancer Research, Japan (1977); and the Experimental Pathological Research Association, Japan (1977).

² To whom requests for reprints should be addressed.

³ Sponsored by the U.S.-Japan Cooperative Cancer Research Program. Present address: Departments of Pathology, St. Vincent Hospital and the University of Massachusetts Medical School, Worcester, Mass. 01610.

Received 9/26/77. Accepted 3/ 1/78.