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The National Heart, Lung, and Blood Institute funds angiogenesis-related extramural research aimed at improving the understanding of normal and abnormal angiogenesis and translating mechanistic findings into therapeutic interventions. This portfolio analysis of fiscal years 2008 through 2015 shows that the National Heart, Lung, and Blood Institute awarded an average of 229±26 angiogenesis-related grants with an average cost of $116±20 million per fiscal year. Angiogenesis research was funded through 4 major funding mechanisms, mainly through Research Project Grants (R01s, 64% of the total awards). New awards (type 1) that may represent pursuit of new directions in angiogenesis research accounted for an average of 19±3% of total awards per fiscal year. In the portfolio, 74.1% of awards (65% of total dollars) used in vivo animal models; 9.7% of awards (5% of total dollars) used in vitro methods; 13.7% of awards (27% of total dollars) involved human subject studies (not including clinical trials); and 2.5% of awards (3% of total dollars) supported clinical trials. Public impact was measured by the annual average number of publications per grant (3.3±0.3) and cost ($154±24 thousand) per publication. Our analyses revealed that intussusceptive angiogenesis may represent an understudied mechanism, and therapeutic angiogenesis remains a remarkable challenge and opportunity to treat angiogenesis-related diseases. Angiogenesis denotes the process of new blood vessel formation and growth that is vital for normal embryonic development, patterning of the vascular system, and wound healing. Insufficient, excessive, or aberrant angiogenesis may have significant clinical consequences in diseases, such as stroke, myocardial infarction, cancer, chronic inflammation, and retinopathy.1 These key contributions to physiological and pathological processes support the high significance of research aimed at better understanding the complex regulation of angiogenesis. The National Institutes of Health (NIH), the largest funding source for biomedical research in the world, funds angiogenesis-related extramural research (hereafter abbreviated as …

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.

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 —Intussusceptive angiogenesis is a novel mode of blood vessel formation and remodeling, which occurs by internal division of the preexisting capillary plexus without sprouting. In this study, the process is demonstrated in developing chicken eye vasculature and in the chorioallantoic membrane by methylmethacrylate (Mercox) casting, transmission electron microscopy, and in vivo observation. In a first step of intussusceptive angiogenesis, the capillary plexus expands by insertion of numerous transcapillary tissue pillars, ie, by intussusceptive microvascular growth. In a subsequent step, a vascular tree arises from the primitive capillary plexus as a result of intussusceptive pillar formation and pillar fusions, a process we termed “intussusceptive arborization.” On the basis of the morphological observations, a 4-step model for intussusceptive arborization is proposed, as follows: phase I, numerous circular pillars are formed in rows, thus demarcating future vessels; phase II, formation of narrow tissue septa by pillar reshaping and pillar fusions; phase III, delineation, segregation, growth, and extraction of the new vascular entity by merging of septa; and phase IV, formation of new branching generations by successively repeating the process, complemented by growth and maturation of all components. In contrast to sprouting, intussusceptive angiogenesis does not require intense local endothelial cell proliferation; it is implemented primarily by rearrangement and attenuation of the endothelial cell plates. In summary, transcapillary pillar formation, ie, intussusception, is a central and probably widespread process, which plays a role not only in capillary network growth and expansion (intussusceptive microvascular growth), but also in vascular plexus remodeling and tree formation (intussusceptive arborization).