By using transparent chambers in rats, we have directly observed tumor‐induced neovascularization in the early stage and the formation of intricate networks in Yoshida rat ascites hepatoma AH109A and Sato lung carcinoma at high magnification. We counted branching point numbers per unit area in the microvascular network with and without tumors in order to clarify the sites from which new vascular sprouts originate. Branching point number per unit area in normal tissue was 13.6 ± 7.4/0.1 mm2 in the field near a terminal arteriole, and 12.9 ± 7.3/0.1 mm2 in the field distant from a terminal arteriole. There was no significant difference between these two fields in the normal vascular network. On the other hand, in the tumor vascular network, the branching point number in the field near a terminal arteriole was 50.4 ± 12.6/0.1 mm2, and 30.1 ± 11.5/0.1 mm2 in the field distant from a terminal arteriole. The difference is highly significant (P<0.001). The frequency with which new capillaries originated from veins and venules was very low. We concluded from these results that the position from which tumor vessels originated was usually the terminal portion of a terminal arteriole.

To elucidate the significance of angiotensin II (AID‐induced hypertension chemotherapy, changes of tissue blood flow both in normal subcutis and in tumors (AH109A, LY80) were measured with the hydrogen gas clearance method. A newly‐developed anesthetic machine was used to keep the animals' condition constant. Tissue blood flow in normal subcutis and tumors always fluctuated with time under normotension. The nature and the rate of fluctuation in tumor Wood flow were almost identical in two different types of tumors. However, the fluctuation of blood flow in tumor and that in normal subcutis were almost always inversely related when blood flows in these different tissues were measured simultaneously, i.e., when tissue blood flow in normal subcutis decreased, tumor blood flow increased, and vice versa. The findings supported the idea that the connection mode between the tumor vascular bed and normal vascular bed is a parallel circuit. Vascular resistance in the normal vascular bed under All‐induced hypertension seemed to be greater than that under normotension, because the All‐increased tumor blood flow always exceeded the maximum tumor blood flow under normotension. Due to the fluctuations of tumor blood flow, no‐flow or low‐flow areas, resistant to delivery of anti‐cancer drugs, moved sporadically within the tumor under the normotensive condition. However, good conditions for drug delivery to tumor tissue were induced by All‐induced hypertension.

Abstract-To investigate mechanisms of vascular morphogenesis in tissue repair, we performed ovariectomy with resection of the corresponding branches of the ovarian vessels in nude mice. This induces a vascular network remodeling response in the healing ovarian pedicle. Reconstruction of 2000 histological serial sections demonstrated that a new vascular network composed of venous-venous loops forms in the wall of the dilated ovarian vein. Preexisting veins of all sizes, including a branch of the main artery, are subjected to segmentation. Loop formation and segmentation are based on intussusceptive microvascular growth. Loop formation is followed by elongation. Loop remodeling occurs also by intussusception and results in the formation of compound loop systems. All loop systems observed were completely patent. Blind-ending sprouts were extremely rare. Anastomoses between the preexisting vessels subjected to segmentation and the loop systems were established to include the newly formed vessels into the preexisting vascular network. The formation of an increasing number of patent loop systems likely decreases hypoxia and subsequently arrests angiogenesis with transformation of the granulation tissue into a scar. Loop formation also occurred inside a large thrombus that occluded a part of the lumen of the main vein.

Abstract-To determine mechanisms of blood vessel formation and growth in solid tumors, we used a model in which LS174T human colon adenocarcinomas are grown in the isolated ovarian pedicle of nude mice. Reconstruction of 3500 histological serial sections demonstrated that a new vascular network composed of venous-venous loops of varying sizes grows inside the tumor from the wall of the adjacent main vein. Loops elongate and remodel to establish complex loop systems. The mechanisms of loop formation and remodeling correspond to intussusceptive microvascular growth (IMG). In the tissue surrounding the tumor segmentation, another mechanism of IMG is prevalent in venous vessels.Comparison to vascular morphogenesis in the ovariectomized pedicle not only confirms the existence of corresponding mechanisms in both systems, but also reveals numerous sprouts that are superimposed onto loop systems and pathological deviations of loop formation, remodeling, and segmentation in the tumor. These pathological mechanisms interfere with vessel patency that likely cause heterogenous perfusion and hypoxia thus perpetuating angiogenesis. Blood vessel formation based on IMG was also detected in a large thrombus that completely occluded a part of an ovarian artery branch. Key Words: angiogenesis Ⅲ colon adenocarcinoma (LS174T) Ⅲ endothelial cell Ⅲ intussusceptive microvascular growth Ⅲ restenosis T he formation of sprouts in angiogenesis 1,2 has been widely accepted as a basic mechanism of angiogenesis in wound healing 3-5 and tumors. 6 Another mechanism of vascular morphogenesis termed intussusceptive microvascular growth (IMG) has been identified in many organs and different species. [7][8][9][10][11][12][13][14][15][16][17] Intussusception involves growth and remodeling of the vascular system based on partitioning of the vessel lumen by columns of tissue, called tissue pillars or posts (diameter Ͻ2.5 m) and interstitial or intervascular tissue structures (ITSs, diameter Ͼ2.5 m). Evidence for IMG in pathological states comes from findings that intussusception is induced by tumor ascites fluid in peritoneal lining tissues. 18 It has also been suggested that the remodeling of vascular branching points during tumor angiogenesis be implemented by IMG. 19 In the first in vivo documentation of IMG in solid tumors, we demonstrated basic mechanisms of its implementation and its coexistence with sprout-like structures. Our data showed that the network architecture in tumors changes on a time scale of minutes based on frequent remodeling by IMG. This might explain intermittent blood flow. 14 In the present study, we analyzed histological serial sections to reconstruct the architecture of the vascular network of human colon adenocarcinomas (LS174T) transplanted onto the isolated ovarian pedicle of nude mice. 20,21 Two new mechanisms of blood vessel formation based on IMG were identified: in situ loop formation and remodeling, which give rise to a new vascular network inside the tumor and segmentation that expands and remodels the preexisting ...