Engineering of Blood Vessel Patterns by Angio-Morphogens [Angiotropins]:. Non-Mitogenic Copper-Ribonucleoprotein Cytokines [CuRNP Ribokines] with their Metalloregulated Constituents of RAGE-binding S100-EF-Hand Proteins and extracellular RNA Bioaptamers in Vascular Remodeling of Tissue and Angiogenesis in vitro

Abstract

Tissue vascularization is requisite to successful cell‐based therapies, biomaterial design and implant integration. Thus, known problems in ossointegration of avascular implants in connection with the generation of bone tissue reflect arrays of general problems of socio‐economic relevance existing in reparative medicine still waiting for to be solved. For this purpose, morphogenesis and remodeling of endothelial angio‐architectures in tissue and in vitro by isolated non‐mitogenic angio‐morphogens [angiotropins] are considered in terms of their structure, function and action mechanisms. Extracellular angiotropins are secreted by activated leukocytes/monocytes/macrophages. They are a family of cytokines with morphogen bioactivity selectively directed to endothelial cells. Their structure was deciphered as metalloregulated copper‐ribonucleoproteins [CuRNP ribokines]. They are built up of angiotropin‐related S100‐EF‐hand protein [ARP] and highly modified and edited 5'end‐phosphorylated RNA [ARNA], complexed together by copper ions. Oxidant‐sensitive ARNA and their precursors represent novel types in a RNA world: They are the first isolated and sequenced forms of extracellular RNA [eRNA], may act as cytokine and bioaptamer, contain isoguanosine [crotonoside] as modified nucleoside and show up copper as RNA‐structuring transition metal ion. By metalloregulated bioaptamer functions, ARNA impart novel biofunctions to RAGE‐binding S100‐EF‐hand proteins. Angiotropin morphogens were shown suitable for neointiation and remodeling of blood vessel patterns in different, adult, embryonal and artificial tissues. These neovascular patterns manifest regulated hemodynamics for preventing tissue necrosis, supporting tissue functions and promoting wound healing. As evaluated in skin and muscle vascularization, the neovascular patterns are integrated into homeostatic control mechanisms of tissue. Thus, the morphogens show up beneficial perspectives and are suggested useful tools for further investigations in angiotherapy, engineering of blood vessel patterns in tissues and biocompatible artificial organs as well as in the preparation of novel implants with morphogen‐coated surfaces.

Engineering of Capillary Patterns in Muscle by a Nonmitogenic Copper‐Ribonucleoprotein Angiomorphogen [Angiotropin CuRNP Ribokine]

“…The 99 Tc distribution appears almost as rapid and intense as in the large axial vessels of the body. Other techniques could show that dynamics of flow are a property of newly formed three‐dimensional networks of capillaries in tissue2‐4,7‐13 (e.g., by making capillary structures and functions accessible to visual inspection by microparticle distribution and to characterization by laser Doppler‐flow velocimetry).…”

“…It was purified from serum‐free culture supernatants of isolated, lectin‐activated porcine (mononuclear) leukocytes. The biotechnical and bioreactor details are described elsewhere 3,4,13. For preliminary experiments, the same AT was isolated from wound fluids (homogenates) of ischemic or infarcted inflamed heart muscle sites in dog and pig 24 h after occlusion of the left anterior descending branch of left coronary artery by transfemoral catherization 2,12.…”

“…Thus, modes of application of an angiomorphogen in the form of angiotropin (AT) ribokine into muscle were investigated. Members of human and porcine AT cytokine (ribokine) family represent endogenous nonmitogenic endothelial cell‐selective and vascularizing morphogens of leukocytic origin 2‐13. They are extracellular copper‐ribonucleoprotein complexes (CuRNP) built up of copper ion, metalloregulated AT‐related protein (ARP), and of extracellular eRNA bioaptamer units (ARNA, 72‐78 nucleotides) of defined sequences.…”

“…EFVVL is part of an exposed ARP epitope for a polyclonal antibody 5. The cluster of Ca, Na, K ions and H 2 O is schematic for multiple stoichiometric ratios 4,13. In ARNA, N are modified bases; among these is isoguanine (151 Da).…”

“…It suggests AT, ARP, ARNA, and ions as components of a Fenton‐redox reaction type, OH*‐radical‐dependent and metalloregulated biomolecular switch operative in vascular remodeling. A more detailed description is presented elsewhere 4‐6,13…”