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In: Drug Discovery Today: Disease Models, Vol. 8, No. 1, 2011, p. 1-3.
Research output: Contribution to journal › Editorial › peer-review
TY - JOUR
T1 - Proteolytic degrading processes in the microcirculation
AU - Schmid-Schönbein, Geert W.
AU - Lipowsky, Herbert H.
N1 - Funding Information: Geert W. Schmid-Schönbein 1 ⁎ firstname.lastname@example.org Herbert H. Lipowsky 2 email@example.com 1 University of California San Diego, Department of Bioengineering, Powell-Focht Bioengineering Hall, La Jolla, CA 92093-0412, USA 2 Penn State University, Department of Bioengineering, University Park, PA 16802, USA ⁎ Corresponding author. The structure and function of the microvasculature are linked by a broad spectrum of developmental and homeostatic mechanisms that revolve around the pivotal role of extra- and intracellular proteases. It has been reported that nearly 2% of mammalian genes encode proteases and that proteases represent between 5 and 10% of drug targets (Overall, C.M. and Blobel, C.P., Nat. Rev. Mol. Cell Biol. 8(3): 245–257, 2007). In the five decades that have passed since recognition of the importance of protease activity in affecting the microvasculature (Zweifach et al. , J. Exp. Med. 113: 437–450, 1961) genomic, proteomics and biochemical analyses have identified over 500 proteases spread across five major families (aspartate, cysteine, metallo, serine and threonine proteases) which act as effectors of physiological responses. Their involvement in several major human diseases is recognized today, but only in a partial picture that does not fully describe the role proteases play in disease etiology and therefore has not facilitated development of rational intervention in many diseases. This issue of Drug Discovery Today: Disease Models explores recent developments in studies of the effects of proteolytic processing on microvascular networks during angiogenesis and architectural remodeling and in response to pathological conditions, such as diabetes, hypertension and inflammation. Within the broad spectrum of proteases that may affect progression of the disease process, the metalloproteases, typically associated with remodeling of the extracellular matrix and hence readily identified as matrix metalloproteases (MMPs), have received considerable attention in multiple organs. Typically identified by the activity of their catalytic zinc domain, these proteases are highly visible targets in the development of pharmaceuticals. Gorman and Haas review the mechanisms through which MMP activation, phosphorylation and oxidation/nitrosylation are regulated by transcriptional, post-transcriptional and post-translational events. Also, the role of endogenous inhibitors of MMP activation present in tissues, the so-called TIMPs is discussed, with a focus on physiological and pathological roles of vascular MMPs. It is now recognized that proteinases play a key role during angiogenesis. In the article by Davis, the major functions of proteinases are discussed in light of development of the microvascular network via angiogenic sprouting and formation of vascular tubes by the process of morphogenesis. The essential roles of proteases in degrading the extracellular matrix to facilitate invasion of vascular sprouts and concomitant morphological changes are reviewed. The specificity of membrane type MMPs that are associated with the endothelial cell membrane (e.g. MT1-MMP) is explored in light of its role in tubulogenesis. Also Davis explores the mechanisms underlying proteinase-dependent modulation of angiogenesis and the influence on cell surface molecule shedding, initiation of angiogenic sprouting and inactivation of proteinase inhibitors. The role of MMP activity in the remodeling of small arteries, as occurs in many forms of hypertension, is explored in the review by Martinez-Lemus and Galinanes. They give an overview of the known and potential roles that MMPs have on vascular remodeling, with particular attention to their action during inward eutrophic remodeling process of small resistance arteries that occurs in hypertension. This unique mode of inward growth of the small vessel wall appears to occur without changes in the amount of constituents of the wall itself and is associated with an up-regulation of MMP expression. Models of the inward eutrophic remodeling of resistance vessels are discussed in essential hypertension, vasoconstriction-induced hypertension and renovascular hypertension. There is emerging evidence that agonist-activated metalloproteinases exhibit different expression patterns and mutual transcriptional regulation during the development of hypertension and cardiac remodeling. To review recent developments in this area, Bosonea et al. have explored the role of proteases as signaling mediators in agonist-induced hypertension and cardiac remodeling. When agonists bind to cognate receptors on the cell membrane, activation of phospholipases results in a chain of events leading to the generation of reactive oxygen species, which in turn activate multiple MMPs. Numerous signaling mechanisms attendant to MMP activation are initiated which affect disease development and contribute to regulation of activation of multiple members of the family of metalloproteinases, thus leading to a broad spectrum of expression and varying physiological roles in hypertension and cardiovascular disease. It is readily apparent that the metalloproteinases act as a transduction point for multiple signaling systems and a molecular communication network that governs a great variety of physiological processes. In the review by Delano et al. , the multifaceted roles of extracellular proteases are clearly brought into focus in light of their effect on the etiology of diabetes and hypertension. A new mechanism for the diverse cellular and organ derangements peculiar to these disorders is proposed in view of recent findings on uncontrolled protease activity, derived in part from serine proteases and MMPs. Proteolytic cleavage of numerous receptors in animal models of hypertension (the spontaneously hypertensive rat, SHR) suggest a key role for derangements in receptors which govern adrenergic activity, insulin transport and integrin signaling, which are derived from unchecked and errant protease activity. Evidence from studies of the SHR is reviewed that suggests that proteases may be responsible for dysfunction of multiple receptor (e.g. adrenergic receptors) causing arteriolar constriction and hypertension, the insulin receptor, producing insulin resistance and type II diabetes, and vascular endothelial growth factor receptor, which enhances apoptosis of constituents of the microvascular wall and leads to microvascular rarefaction. Protease activity may also result in derangements of the formyl-peptide receptor on the endothelium which adversely affects flow mediated pseudopod retraction, and degradation of junctional proteins that bind endothelial cells together to maintain structural integrity of the microvascular wall. The ubiquitous presence of proteases is strikingly apparent in the function of mast cells. In the review by Dai and Korthuis the role of mast cell proteases in the inflammatory process is reviewed in light of a diverse array of disorders (e.g. asthma, arthritis, aneurysms, intimal hyperplasia, ischemia/reperfusion injury) and essential homeostatic processes (e.g. innate immune responses, adaptive immunity, ischemic preconditioning) to which they contribute. Mast cell mediators include an array of cytokines, biogenic amines, proteoglycans and glycosaminoglycans, as well as mast cell specific proteases, including the serine proteases chymase and tryptase, and the zinc dependent metalloproteinase carboxypeptidase A. It is noted that mast cell proteases are present in their fully active form and can immediately contribute to tissue injury when released upon mast cell degranulation. In vitro and in vivo models for elucidating the key role of these proteases in inflammation are reviewed and highlight the central role that mast cells play in the inflammatory process. Finally, this issue concludes with a review by Lipowsky of evidence for a new model of the role of extracellular proteases in the onset of inflammation at the interface between blood and the microvascular endothelium. Based upon observations in experimental models of the onset of inflammation, it is hypothesized that activation of MMPs within the endothelial cell, or present on its luminal surface, degrades the layer of polysaccharides on the endothelial surface, the glycocalyx, which in turn exposes leukocyte adhesion receptors to promote firm adhesion of leukocytes to the microvascular wall. Evidence is reviewed that demonstrate the concurrent activation of MMPs within the glycocalyx, shedding of glycans from the endothelial surface, and enhanced leukocyte adhesion during a model of inflammation using chemoattractants. Thus, with this array of focused studies that employ models of the pathological processes of microvascular remodeling, hypertension, diabetes and inflammation, we aim to stimulate an appreciation for the pivotal role of extracellular proteases in affecting microvascular derangements as the basis for development of new interventions. It is hoped that these reviews stimulate further investigations into pivotal events that control extracellular proteases and their activity in health and disease. Even the casual reader will recognize that there are numerous untapped opportunities. Geert W. Schmid-SchönbeinHerbert H. Lipowsky Geert W. Schmid-Schönbein is Distinguished Professor and Director of the Microcirculation Laboratory in the Department of Bioengineering at UCSD. He received his Ph.D. degree in Bioengineering at UCSD. After three years as Post-doctoral Fellow in the Department of Physiology of Columbia University, New York, he joined the faculty of the Department of Bioengineering at UCSD in 1979 where he has served ever since. He teaches bioengineering of living tissues and biomechanics and has been nominated repeatedly as Teacher of the Year in Bioengineering at UCSD. He is member of many learned Societies in Engineering and in Medicine, Founding Member of AIMBE, former President of the Biomedical Engineering Society, the Microcirculatory Society and the North American Society of Biorheology, Fellow of the American Heart Association and the International Federation for Medical and Biological Engineering, and Member of the National Academy of Engineering. He is Chair of the World Council for Biomechanics and the US National Committee on Biomechanics. His research interest is in Microcirculation, Cell and Molecular Mechanics applied to pathophysiology and inflammation. His team carries out engineering analysis of human disease and has discovered a mechanism for cell dysfunctions because of ‘Auto-digestion’. The team proposed a previously unrecognized mechanism for Shock and Multi-organ Failure as well as Type II Diabetes, Hypertension and Metabolic Syndrome X. Herbert H. Lipowsky is Professor of Bioengineering and founding Chair of the Department of Bioengineering at Penn State University. His research focuses on how the rheological properties of blood, and blood cell interactions with the endothelium, affect perfusion of the microvascular network. He received his Ph.D. in Bioengineering from UC San Diego. During the past 35 years, he has developed and applied numerous techniques using intravital microscopy to study blood flow in the capillary network of exteriorized tissues in anesthetized animals. His recent interests have focused upon the role of the endothelial glycocalyx as a barrier to leukocyte-endothelium adhesion during the inflammatory process, and interactions between the structure of the glycocalyx and hemodynamic factors that affect its composition. He is a past-president of the US Microcirculatory Society and the Biomedical Engineering Society, and is currently president of the International Society of Biorheology.
PY - 2011
Y1 - 2011
UR - http://www.scopus.com/inward/record.url?scp=82455164243&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=82455164243&partnerID=8YFLogxK
U2 - 10.1016/j.ddmod.2011.07.006
DO - 10.1016/j.ddmod.2011.07.006
M3 - Editorial
AN - SCOPUS:82455164243
SN - 1740-6757
VL - 8
SP - 1
EP - 3
JO - Drug Discovery Today: Disease Models
JF - Drug Discovery Today: Disease Models
IS - 1