Functional diversity of extracellular matrix components during vessel migration, endothelial sprouting and blood vessel stabilization

The formation of mature blood vessels requires recruitment of mural cells (MC) and generation of an extracellular matrix in order to stabilize and support the nascent vessel. The precise sequence of basement membrane protein expression and function during initiation, elongation and stabilization of the angiogenic sprout remains unclear. The first project describes a function of astrocytic Fibronectin (FN) in guided vessel migration. Integrin-binding is dispensable for fibrilliar FN assembly but mediates endothelial cell adhesion in vivo. VEGF-A dependent migration of retinal vessels requires PI3K activity and astrocytic FN possibly functions to retain VEGF protein on the astrocytic matrix. In a second project we discovered endothelial tip cells-specific expression of laminin alpha4 (Lama4) and provide first evidence for an influence of laminin α4 on endothelial Dll4/Notch signalling in sprouting angiogenesis. Loss of Lama4 leads to increased filopodia formation, tip cell numbers and consequently increased vessel density, resembling the phenotype of disturbed Dll4/Notch signalling. Loss of Lama4 leads to reduced Dll4 and Notch target gene expression, whereas gain-of-function results in increased Dll4 expression in vitro. Preliminary results suggest that laminin α4 induced Dll4 expression involves both VEGFR2 and integrin signalling. The third project addresses the cell-autonomous requirement of heparan sulfate (HS) production by MCs during mouse embryonic vascular development. Conditional deletion of HS synthesis in MC caused severe vascular defects and embryonic lethality. Unexpectedly, distinct regions of vascular growth showed selective requirement for MC HS production: whereas MC recruitment in peripheral skin vascularization is severely disrupted, MCs during brain angiogenesis appear unaffected. Similarly, PDGF-B and TGF-β signalling are impaired in the peripheral vessels, but not in the brain. These data suggest that cell-autonomous HS is essential for MC recruitment in the skin vasculature, where induction and differentiation of local progenitor cells from the mesenchymal cell lineage is mediated by TGF-β signalling

Arteriogenesis and Therapeutic Angiogenesis

Although advances in therapeutic interventions improved outcomes, vascular occlusive diseases are still challenging not only afflicted but also attending physicians, requiring novel therapeutic strategies. Arteriogenesis, sometimes also called therapeutic angiogenesis, refers to the body’s own capacity to create a natural bypass around a narrowing or occluded arterial vessel. This book gives an insight into current knowledge and advances in vascular sciences and future prospects of therapeutic options. The utility and relevance of circulating biomarkers together with the potential of machine learning methods are discussed as well as the challenges and prospects of novel therapies such as protein- gene-, and stem cell therapy along with multicistronic multigene vectors and the use of microRNAs, exosomes, and secretomes. Vascular smooth muscle phenotype switch as a target to promote arteriogenesis is critically addressed, highlighting the problem of promoting atherosclerosis in parallel. Two articles even deal with cold-inducible RNA-binding protein CIRP/CIRPB presenting it as promising target to promote vascularization concomitant the reduction in ischemic tissue damage. BMPR kinase inhibition is introduced to improve tissue repair in a hereditary form of vascular disorder, and the role of the AP-1 transcription factor JunB in blood vessel formation is described. Some more experimental oriented articles deal with the relevance of choosing the appropriate mouse strain for investigations as well as in vitro Matrigel plug assay as a potent method to investigate angiogenesis. Last but not least, two-photon intravital microscopy is presented as suitable tool to assess plaque angiogenesis in atherosclerotic lesions

Molecular Imaging

The present book gives an exceptional overview of molecular imaging. Practical approach represents the red thread through the whole book, covering at the same time detailed background information that goes very deep into molecular as well as cellular level. Ideas how molecular imaging will develop in the near future present a special delicacy. This should be of special interest as the contributors are members of leading research groups from all over the world

Dissecting the Genetic Architecture of Complex Traits: Hot Spots and Vascular Collaterals

Collateral arteries are endogenous “bypass vessels” that minimize tissue injury during arterial obstruction. Recent studies from our laboratory demonstrate that wide variation exists among individuals in the extent (number and diameter) of native (pre-existing) collaterals in healthy tissue and their outward remodeling (increase in anatomic diameter) in obstructive disease. Evidence suggests this variation contributes importantly to the wide variation in thromboembolic stroke, ischemic heart disease and peripheral arterial disease in humans. We hypothesized that genetic components contribute significantly to this variation. We tested this hypothesis in 243 C57BL/6 X BALB/c (CXB) F2 mice, wherein number and diameter of native cerebral collaterals and collateral remodeling after middle cerebral artery occlusion (MCAO) were measured. Linkage analysis identified a major QTL on chromosome 7 (Canq1) responsible for more than 30% of the variation in collateral extent. Three additional QTL were obtained for collateral number. Analysis of chromosome substitution and CXB recombinant inbred strains confirmed the dominant role of the Canq1 locus. We also identified a QTL on chromosome 11 linked to variation in collateral remodeling. Efficient mix model association mapping (EMMA) of collateral number among 15 inbred strains delineated 172k (p=0.00002) and 290k (p=0.0004) base-pair regions containing 2 and 7 candidate genes, respectively, within Canq1. Analysis of six additional inbred strains, chosen according to their haplotype within the 172 kb EMMA region, strengthened and narrowed the locus from 172 kb interval to 2 kb. In candidate gene analyses, we found that collateral extent, infarct volume after MCAO, bleeding and re-bleeding times did not differ between Itgal-/,-IL4-/- or IL4-receptor-α-/- and wildtype mice. mRNA expression of 120 genes within the 95% confidence interval of Canq1, measured in the pial vasculature of C57BL/6 and BALB/c at embryonic day-14.5, -16.5 and -18.5 when the collateral circulation forms, identified 19 differentially expressed genes. These results demonstrate that native collateral extent and collateral remodeling are heritable complex traits, with a highly significant QTL on chromosome 7 governing the majority of the variation in these traits. Furthermore, my work prioritizes a set of genes for future analysis as candidates underlying the process of collateral formation and its variation among individuals

Visual Cortex

The neurosciences have experienced tremendous and wonderful progress in many areas, and the spectrum encompassing the neurosciences is expansive. Suffice it to mention a few classical fields: electrophysiology, genetics, physics, computer sciences, and more recently, social and marketing neurosciences. Of course, this large growth resulted in the production of many books. Perhaps the visual system and the visual cortex were in the vanguard because most animals do not produce their own light and offer thus the invaluable advantage of allowing investigators to conduct experiments in full control of the stimulus. In addition, the fascinating evolution of scientific techniques, the immense productivity of recent research, and the ensuing literature make it virtually impossible to publish in a single volume all worthwhile work accomplished throughout the scientific world. The days when a single individual, as Diderot, could undertake the production of an encyclopedia are gone forever. Indeed most approaches to studying the nervous system are valid and neuroscientists produce an almost astronomical number of interesting data accompanied by extremely worthy hypotheses which in turn generate new ventures in search of brain functions. Yet, it is fully justified to make an encore and to publish a book dedicated to visual cortex and beyond. Many reasons validate a book assembling chapters written by active researchers. Each has the opportunity to bind together data and explore original ideas whose fate will not fall into the hands of uncompromising reviewers of traditional journals. This book focuses on the cerebral cortex with a large emphasis on vision. Yet it offers the reader diverse approaches employed to investigate the brain, for instance, computer simulation, cellular responses, or rivalry between various targets and goal directed actions. This volume thus covers a large spectrum of research even though it is impossible to include all topics in the extremely diverse field of neurosciences

Extracellular Matrix in Development and Disease

The extracellular matrix in development and disease deals with the molecular and cellular aspects of development and disease. Cells exist in three-dimensional scaffolding called the extracellular matrix. The matrix holds together the millions of cells that make up our blood vessels, organs, skin, and all tissues of the body. The matrix serves as a reservoir of signaling molecules as well. In bacterial cultures, biofilms form as an extracellular matrix and play essential roles in disease and drug resistance. Topics such as matrix structure and function, cell attachment and cell surface proteins mediating cell-matrix interactions, synthesis, regulation, composition, structure, assembly, remodeling, and function of the matrix are included. A common thread uniting the topics is the essential nature that the matrix plays in normal development and pathophysiology. Providing new knowledge will lead us to improved diagnostics, the preventions of disease progression, and therapeutic strategies for the repair and regeneration of tissues. Topics such as the extracellular matrix in hereditary diseases, reproduction, cancer, muscle, and tissue engineering applications, and diverse roles for integrins, are included in this collection