Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

http://www.chem.uwec.edu/Chem454/BiochemDiabetes.pdf

Biochemistry and molecular cell biology of diabetic complications

Cell signaling by receptor-tyrosine kinases

Endothelial and smooth muscle cells interact with each other to form new blood vessels. In this review, the cellular and molecular mechanisms underlying the formation of endothelium-lined channels (angiogenesis) and their maturation via recruitment of smooth muscle cells (arteriogenesis) during physiological and pathological conditions are summarized, alongside with possible therapeutic applications.

Mechanisms of angiogenesis and arteriogenesis.

Blood vessels constitute the first organ in the embryo and form the largest network in our body but, sadly, are also often deadly. When dysregulated, the formation of new blood vessels contributes to numerous malignant, ischemic, inflammatory, infectious and immune disorders. Molecular insights into these processes are being generated at a rapidly increasing pace, offering new therapeutic opportunities that are currently being evaluated.

Angiogenesis in health and disease.

A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.

Vascular-specific growth factors and blood vessel formation

Angiogenesis is thought to depend on a precise balance of positive and negative regulation. Angiopoietin-1 (Ang1) is an angiogenic factor that signals through the endothelial cell-specific Tie2 receptor tyrosine kinase. Like vascular endothelial growth factor, Ang1 is essential for normal vascular development in the mouse. An Ang1 relative, termed angiopoietin-2 (Ang2), was identified by homology screening and shown to be a naturally occurring antagonist for Ang1 and Tie2. Transgenic overexpression of Ang2 disrupts blood vessel formation in the mouse embryo. In adult mice and humans, Ang2 is expressed only at sites of vascular remodeling. Natural antagonists for vertebrate receptor tyrosine kinases are atypical; thus, the discovery of a negative regulator acting on Tie2 emphasizes the need for exquisite regulation of this angiogenic receptor system.

https://science.sciencemag.org/content/sci/277/5322/55.full.pdf

Angiopoietin-2, a Natural Antagonist for Tie2 That Disrupts in vivo Angiogenesis

The angiopoietins have recently joined the members of the vascular endothelial growth factor family as the only known growth factors largely specific for vascular endothelium. The angiopoietins include a naturally occurring agonist, angiopoietin-1, as well as a naturally occurring antagonist, angiopoietin-2, both of which act by means of the Tie2 receptor. We now report our attempts to use homology- based cloning approaches to identify new members of the angiopoietin family. These efforts have led to the identifica- tion of two new angiopoietins, angiopoietin-3 in mouse and angiopoietin-4 in human; we have also identified several more distantly related sequences that do not seem to be true angiopoietins, in that they do not bind to the Tie receptors. Although angiopoietin-3 and angiopoietin-4 are strikingly more structurally diverged from each other than are the mouse and human versions of angiopoietin-1 and angiopoi- etin-2, they appear to represent the mouse and human coun- terparts of the same gene locus, as revealed in our chromo- somal localization studies of all of the angiopoietins in mouse and human. The structural divergence of angiopoietin-3 and angiopoietin-4 appears to underlie diverging functions of these counterparts. Angiopoietin-3 and angiopoietin-4 have very different distributions in their respective species, and angiopoietin-3 appears to act as an antagonist, whereas angiopoietin-4 appears to function as an agonist. Two families of growth factors have been identified that are largely specific for the vascular endothelium, by virtue of having receptors that are mostly restricted to endothelial cells in their expression. These include vascular endothelial growth factor (VEGF) and its relatives, as well as the more recently discovered angiopoietins (1, 2). These two families seem to work in complementary and coordinated fashion during vas- cular development, with VEGF acting during the early stages of vessel development (3-5), and angiopoietin-1 (6) acting later to promote angiogenic remodeling as well as vessel maturation and stabilization (7, 8). Simply overexpressing angiopoietin-1 by using transgenic approaches leads to hyper- vascularization in vivo (9), suggesting that angiopoietin-1 is present in limiting quantities during angiogenesis in vivo. Angiopoietin-1 has a naturally occurring antagonist, termed angiopoietin-2, which blocks the ability of angiopoietin-1 to activate its receptor, Tie2 (10). Transgenic overexpression of angiopoietin-2 disrupts normal vascular development and results in early embryonic lethality (10). Angiopoietin-2 is the first example of a natural antagonist for a receptor tyrosine kinase in vertebrates, suggesting that activation of the Tie2 receptor must be particularly well titrated in vivo. Evidence suggests that such careful regulation might be involved at sites of vascular change in an otherwise stable adult vasculature. Thus, whereas angiopoietin-1 appears to be widely expressed in the adult in a manner suggesting that it is acting to stabilize vessels, angiopoietin-2 is expressed only at sites of vascular remodeling in the adult (10). It has been suggested that this expression of the antagonist blocks an otherwise constitutive stabilizing signal provided by angiopoietin-1, leading to local-

Joyce Mcclain

Papers

Angiopoietin-2, a Natural Antagonist for Tie2 That Disrupts in vivo Angiogenesis

Angiopoietins 3 and 4: Diverging gene counterparts in mice and humans (angiogenesisytie receptor tyrosine kinaseyvascular endothelial growth factor)