Background-Tyrosine kinase inhibitors (TKIs) have advanced cancer treatment. Sunitinib, a recently-approved, multi-targeted TKI, prolongs survival for patients with metastatic renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST), but concerns about cardiac safety have arisen with this agent.

Tumor growth is angiogenesis dependent. We hypothesized that nonneoplastic tissue growth also depends on neovascularization. We chose adipose tissue as an experimental system because of its remodeling capacity. Mice from different obesity models received anti-angiogenic agents. Treatment resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Marked vascular remodeling was evident in adipose tissue sections, which revealed decreased endothelial proliferation and increased apoptosis in treated mice compared with controls. Continuous treatment maintained mice near normal body weights for age without adverse effects. Metabolic adaptations in food intake, metabolic rate, and energy substrate utilization were associated with antiangiogenic weight loss. We conclude that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature. Substantial evidence has established that tumor growth is angiogenesis-dependent (1). Neovascularization promotes tumor growth (2), whereas angiogenesis inhibition prevents it, and can regress the lesions (3). This raises the question of whether the endothelium functions similarly in nonneoplastic tissue growth (4).The challenges in addressing this question are that most adult tissues normally do not grow, their mass is stable, and the supporting vasculature is quiescent (5). Exceptionally, adipose tissue can grow and regress throughout adulthood. It is highly vascularized and has angiogenic properties (6, 7). An extensive capillary network surrounds each adipocyte, and there are few other resident cell types (8). Therefore, adipose tissue is uniquely suited to study the role of angiogenesis in nonneoplastic adult tissue growth.The potential for adipose tissue to grow and regress is substantial. One would expect the vasculature to have a commensurate capacity for remodeling. We hypothesized that adipose tissue growth is angiogenesis dependent and, therefore, may be inhibited by anti-angiogenesis agents. This would suggest that adipose tissue mass may be regulated via the vascular endothelium.We primarily used ob͞ob mice because they rapidly accumulate adipose tissue (9). This strain develops spontaneous obesity because of a lack of functional leptin, a protein secreted by adipocytes that acts on the hypothalamus to regulate appetite and metabolism (9-11). Without leptin, animals eat excessively, expend less energy, and become morbidly obese. Leptin replacement induces weight loss in ob͞ob mice by specifically reducing adipose tissue (9), unlike diet restriction or appetite suppression (fenfluramine), which decreases both lean and fat mass (12, 13).We treated ob͞ob mice with various angiogenesis inhibitors. We primarily used TNP-470 (14) because of availability. TNP-470 inhibits endothelial cell proliferation in vitro (15) and angiogenesis in vivo (16). At significantly higher concentrations, TNP-470 can also suppress nonendothelial cell proliferation (14,17). Angiostatin (kringle 1-4 domains of plasminogen) (18) and endostatin (...

Cardiac tissue engineering has been motivated by the need to create functional tissue equivalents for scientific studies and cardiac tissue repair. We previously demonstrated that contractile cardiac cell–polymer constructs can be cultivated using isolated cells, 3‐dimensional scaffolds, and bioreactors. In the present work, we examined the effects of (1) cell source (neonatal rat or embryonic chick), (2) initial cell seeding density, (3) cell seeding vessel, and (4) tissue culture vessel on the structure and composition of engineered cardiac muscle. Constructs seeded under well‐mixed conditions with rat heart cells at a high initial density ((6–8) × 106 cells/polymer scaffold) maintained structural integrity and contained macroscopic contractile areas (approximately 20 mm2). Seeding in rotating vessels (laminar flow) rather than mixed flasks (turbulent flow) resulted in 23% higher seeding efficiency and 20% less cell damage as assessed by medium lactate dehydrogenase levels (p < 0.05). Advantages of culturing constructs under mixed rather than static conditions included the maintenance of metabolic parameters in physiological ranges, 2–4 times higher construct cellularity (p ≤ 0.0001), more aerobic cell metabolism, and a more physiological, elongated cell shape. Cultivations in rotating bioreactors, in which flow patterns are laminar and dynamic, yielded constructs with a more active, aerobic metabolism as compared to constructs cultured in mixed or static flasks. After 1–2 weeks of cultivation, tissue constructs expressed cardiac specific proteins and ultrastructural features and had approximately 2–6 times lower cellularity (p < 0.05) but similar metabolic activity per unit cell when compared to native cardiac tissue. © 1999 John Wiley & Sons, Inc. Biotechnol Bioeng 64: 580–589, 1999.