For some decades, a great need in biomedical research has been the insightful mapping and quantification of vascular remodeling for vascular-dependent diseases such as cancer, diabetes, and coronary vessel disease. Vascular patterning serves as an integrative biomarker principle of multi-scale signaling by complex molecular pathways and mechanical forces. However, the tissue-specific complexity of successive branching generations of multi-scale, fractal-based vascular systems is difficult to characterize and measure. For many decades, vascular systems were assessed within histological sections and other microscopic images as small round circles. One technical challenge is the many length scales encompassed by the branching vascular system. The diameter of the human aorta, for example, is approximately 3.7 centimeters upstream of many successive vessel bifurcations down to the end-stage capillaries (diameter of approximately 10 micrometers). Another vascular mapping challenge is tissue-specific patterning. Patterning of the highly permeable liver sinusoidal capillaries characterized by small avascular spaces, for example, is very different from the thin, essentially impermeable brain capillaries with large avascular spaces that establish the blood brain barrier (BBB).
When viewed as a technical advantage, however, tissue-specific vascular patterning offers an integrative biomarker principle for multi-scale signaling by complex molecular pathways and mechanical forces, and is therefore be useful for pathological, physiological, and therapeutic applications in biomedical and biological research, including ecology. This is due, in part, to the fractal-based fluid mechanics of complex vascular branching observed even in arterial river systems that support efficient filling of tissues or other spaces by branching aqueous transport systems. For example, the human body contains approximately 50,000 protein molecules that constantly react and interact via complicated metabolic, immunological, and other regulatory pathways, in addition to signaling by numerous other molecular families, such as DNA, RNA, lipids (fats), and steroid hormones. Scientists therefore combine sophisticated chemical analysis of phenomena such as variable gene expression by modern genomics with localized expression maps of genes and other molecules generated by clinical and microscopic tissue imaging, including images of the vasculature. The microscopic maps of molecular localization within tissues are necessary for revealing and consequently understanding the anatomical location and function of these molecules and sub-molecular moieties.
Vascular systems are required by all higher terrestrial life forms, including humans, other vertebrates, insects and higher land plants, to achieve chemical transport and communication between spatially distant cells. As two widely different examples that are nonetheless representative of higher metazoan life forms, virtually every cell in the human body must reside within approximately 500 micrometers (microns) of a capillary blood vessel for life support and functional performance. The leaf venation patterns of dicots (higher land plants) such as oak, maple, and Arabidopsis thaliana (thale cress) are unique, and therefore accepted by botanists as taxonomic/phylogenetic identifiers of individual species. NASA's fractal-based VESsel GENeration Analysis (VESGEN) software was therefore developed as a research and technology discovery tool for automated mapping and quantification of tissue-specific remodeling vascular patterns from microscopic and clinical images.
VESGEN was first developed for the analysis of vascular patterning as a semi-automatic Matlab™ prototype by innovator P. Parsons. The software is based on her original experimental observations in angiogenesis research that each molecular stimulator or inhibitor of vascular growth and remodeling, including VEGF, bFGF, TGf-beta1, angiostatin, and triamcinolone acetonide, induces an informative fingerprint or signature vascular pattern that is both spatio-temporally unique and an integrative readout of complex signaling. Past, current, and future applications include vascular-dependent human disease, such as astronaut health complications, diabetes, cancer and coronary vessel disease, experimental animal models, and plant leaves. Without the growth of new blood vessels (i.e., angiogenesis) that enable tumor growth and metastasis, most tumors would remain microscopically small and not become a medical problem. Excessive, abnormal neovascularization and/or vascular dropout and leakage is the major cause of blindness in diabetic retinopathy (DR) and age-related macular degeneration (AMD). Remodeling vasculature provides an insightful read-out of dominant molecular signaling when mapped and quantified by the innovative VESGEN software. Normalization of the vasculature is determined from the response of vascular pattern to therapeutic testing. Numerous disclosures, publications, and peer-reviewed research grant awards document the ongoing development of VESGEN as an innovative systems analysis of vascular patterning.
The three basic types of vascular morphology determined by molecular and mechanical signaling are branching vascular trees (at the scale of larger vessels), continuously connected vascular networks (at the scale of smaller capillary (reticular) vessels), and tree-network composites. These three types of vascular morphology are further modulated into characteristic vascular patterns as tissue-specific and organism-specific structures, such as the human/vertebrate retina, and species-specific vascular patterns in the leaves of higher (dicot) land plants. Typically, in vertebrate (e.g., human) tissues, a major arterial tree branches by successive, complex, irregular vessel bifurcations down to the level of the capillary network, which is the site of metabolic, immune, and other functional exchanges of the blood with the host tissue. Reacted blood is collected by the branching venous tree for transport back to the heart and lungs. Binary (black/white) image representations of 2D trees, networks, and tree-network composites at differing levels of image resolution are currently mapped and quantified automatically by the VESGEN software. Using VESGEN to analyze ophthalmic clinical vascular images, a potential paradigm shift was recently introduced to the understanding and therapeutic development of early-stage progression to provide new regenerative opportunities for human diabetic retinopathy (DR), the major blinding disease for working-aged adults. VESGEN mapped and quantified surprising, homeostatic-like vascular regeneration at an early stage when the vessels grow much more normally than at the late, highly abnormal, neovascularization stage that causes blindness.
Currently, there is a strong emphasis in biomedical research to identify useful biomarkers that characterize both pathological progression and therapeutic intervention, especially when the markers are highly specific and quantifiable. The discoveries on fingerprint or signature vascular patterns by molecular signaling (both endogenous and therapeutic) illustrate that vascular patterning offers one useful, insightful biomarker for the biomedical research and technology toolbox. With VESGEN, in vivo models of vascular patterning were analyzed for angiogenesis, lymphangiogenesis, and intravital blood flow from cellular/molecular levels to higher system levels that include a murine model of infant retinopathy of prematurity (ROP), developing and pathological coronary and placental-like vessel models, progressive intestinal inflammation, growing murine tumors, genetic mutations in the fruit fly wing, and other pathological, physiological, and therapeutically treated tissues of transgenic mice or avian embryos, as well as developing leaves in the major model organism for plant genetics, Arabidopsis thaliana. 
VESGEN uses 8-neighbor pixel connectivity techniques of image processing to analyze the effects of vascular therapeutics and regulators on blood vessel form and function. Moreover, NASA's mandated enterprise—the long-term human exploration of space, including manned missions to Mars—is currently very challenging due to fundamental astronaut health impairments. These include cardiovascular alterations (CVA) such as the hypothesized increased intracranial pressure associated with well-documented post-spaceflight retinal damage, as a recently discovered high-priority effect of microgravity spaceflight, and therefore present a new NASA-defined bioastronautics risk factor. VESGEN technology was therefore developed and proposed as a novel informative tool for assessing changes to retinal vessels after spaceflight and in human bedrest studies that mimic effects of the microgravity space environment.
Although there is previous work published by other researchers that has to some extent measured vessel density or vascular fractal dimension, no other software has achieved the comprehensive, fractal-based, automated, user-interactive analysis of the three basic vascular morphologies (trees, networks, and tree-network composites) based on sectioning the branching tree and mapping the sections into branching generations. VESGEN 2D has already been applied to and documented successfully for important applications in clinical diagnostic images of the human retina and experimental studies of vascular regulators/therapeutics in the avian chorioallantoic membrane (CAM) and yolk sac, the genetically engineered rodent retina and heart, and other 2D tissue types. VESGEN 2D is a mature beta-level software requested by researchers around the world for many vascular applications.
Typically, VESGEN maps up to twelve (or sometimes more—up to 99 are currently allowed) generations of vascular branching (G1, G12) that may originate from a single parent vessel or multiple parent vessels. Quantification parameters include associated repertoires of vessel diameter, length, number, branch points, density, and fractal dimension (and more), specified to specific branching generations. VESGEN vascular mappings, and hence VESGEN quantification, are based on a defined system of physiological and anatomical rules for fractal-based vascular branching and vessel networks that support aqueous continuity requirements. However, an improved version of VESGEN that facilitates the coordination of essentially unlimited numbers of bioinformatics dimensions for specific molecular and other co-localizations with spatiotemporal dimensions of vascular morphology, and/or that applies geometric principles of translational versus rotational principles for vascular branching to support the transformation of VESGEN 2D to VESGEN 3D, may be beneficial.
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