Heparin/Heparan Sulfate Proteoglycans Glycomic Interactome in Angiogenesis: Biological Implications and Therapeutical Use

Abstract

Angiogenesis, the process of formation of new blood vessel from pre-existing ones, is involved in various intertwined pathological processes including virus infection, inflammation and oncogenesis, making it a promising target for the development of novel strategies for various interventions. To induce angiogenesis, angiogenic growth factors (AGFs) must interact with pro-angiogenic receptors to induce proliferation, protease production and migration of endothelial cells (ECs). The action of AGFs is counteracted by antiangiogenic modulators whose main mechanism of action is to bind (thus sequestering or masking) AGFs or their receptors. Many sugars, either free or associated to proteins, are involved in these interactions, thus exerting a tight regulation of the neovascularization process. Heparin and heparan sulfate proteoglycans undoubtedly play a pivotal role in this context since they bind to almost all the known AGFs, to several pro-angiogenic receptors and even to angiogenic inhibitors, originating an intricate network of interaction, the so called “angiogenesis glycomic interactome”. The decoding of the angiogenesis glycomic interactome, achievable by a systematic study of the interactions occurring among angiogenic modulators and sugars, may help to design novel antiangiogenic therapies with implications in the cure of angiogenesis-dependent diseases.

Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1

“…They induce EC p38 and JNK activation, increase immune cell adhesion molecule expression, promote VSMC migration, and cause EC barrier dysfunction, all of which further accelerate local inflammation (38,39). A number of studies have determined that heparin exhibits anti-inflammatory properties and modulates angiogenesis (1). Low molecular weight heparin has been shown to reduce JNK and p38 activation, downstream transcription factor activation, and induction of cell adhesion molecule expression (27).…”

“…Many heparin binding proteins, including quite a few involved in modulating vascular function, inflammation, and angiogenesis, have been identified (reviewed in Ref. 1). The large number of reports indicating evidence of decreased endogenous heparin and heparan sulfates (HS) 3 in atherosclerosis (in model animals and human disease) led to a proposal that decreases in endogenous heparins might be important in the development of atherosclerosis (2).…”

“…5). Heparin binding to growth factors modulates their activity and appears to protect them from degradation, whereas HSPGs in the extracellular matrix serve as a reservoir of protected growth factors believed to facilitate wound repair after cellular damage (1,5). Interactions of matrix glycoproteins with cell HSPGs (syndecans and glypicans) in cell membranes contribute to appropriate cellular interactions with the matrix (6,7).…”

Regulation of Protein-Carbohydrate Interactions in Bacteria and Fungi

“…Therefore, it becomes cumbersome to demonstrate the relevance and importance of protein-carbohydrate interaction in the Submit your Manuscript | www.austinpublishinggroup.com assessment of the molecular mechanisms which are contributory to the production and undergirding of protein-carbohydrate complexes, as well as configure a paradigm or design for potent protein-carbohydrate interaction inhibitors, and synthesis [37,43]. In addition to the elucidation of these factors, it is pertinent for future studies to conduct more research on cell surface [42] glycogen composition and synthesis, cell-cell communities, hostpathogen interactions and therapeutics [44]; modification of cell wall biosynthetic pathways; application of biochemical, cellular and molecular as well as bioinformatics methods, biophysical techniques and microbial mutants; and the genes and enzymes related in the regulation [37,43] of cell wall phenomena in response to environmental alterations. Nature utilizes posttranslational modifications to produce an expansive library of complex biological functions.…”

Old and new applications of non-anticoagulant heparin

“…The early reports of the beneficial effects of heparin in inflammation were attributed to the heparin binding and inhibition of chemokines, complement, growth and angiogenic factors, as reviewed recently [1,5,6,7]. Heparin can also bind to adhesion mediators expressed during inflammation, such as selectins, integrins and their receptors [8,9].…”