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ADAM-Mediated Shedding and Adhesion: a Vascular Perspective

Barbara Herren

Cardiovascular Research Division, Institute of Physiology, University of Zurich, CH-8057 Zurich, Switzerland

	Abstract

 
Proteolytic conversion (shedding) of membrane-bound proteins to soluble forms is a novel regulatory mechanism mediated by enzymes called a disintegrin and metalloproteases (ADAMs). In this review, the potential importance of ADAMs in vascular physiology and disease, especially in relation to atherosclerosis, will be highlighted.

	Introduction

Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 
The onset of atherosclerosis is marked by an inflammatory response, induced by an injury of the endothelial monolayer that lines the blood vessels through factors such as oxidized low-density lipoprotein, reactive radical species, or viruses. The endothelial injury precipitates the recruitment of leukocytes to the vessel wall. The process of leukocyte recruitment involves a sequence of multiple adhesive events mediated by different classes of adhesion molecules on activated endothelium and leukocytes. Although the changes in adhesion molecule expression during leukocyte and endothelial activation are well studied, a novel mechanism regulating leukocyte influx has only recently been discovered, a mechanism that consists of the proteolytic cleavage of adhesion molecules by a particular type of cell-associated metalloprotease, a process called shedding. This article reviews and discusses the roles of adhesion molecule shedding and the functions of the specific family of metalloproteases mediating this process in the context of vascular physiology and disease.

	Leukocyte recruitment and adhesion molecule shedding

Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 
Atherosclerosis is accompanied by increased levels of soluble adhesion molecules such as vascular cell or intracellular adhesion molecule-1 (VCAM-1 and ICAM-1, respectively) in the blood. Since these adhesion molecules are involved in the recruitment of leukocytes to sites of vascular injury, their regulation is important in lesion development. Factors associated with atherosclerosis that upregulate expression of these adhesion molecules are well studied. However, the contribution of the release of these transmembrane molecules from the cell surface by controlled cleavage, a process called shedding, is not well understood, although this particular regulatory pathway may be critical to the inflammatory process in atherosclerosis and may provide novel targets for therapeutic intervention. Of particular interest are the contrasting roles of systemic shedding of L-selectin in reducing leukocyte adhesion and of the focal, induced shedding of endothelial adhesion molecules in promoting leukocyte influx and subsequent lesion formation.

	Adhesion molecule shedding from vascular cells: systemic and focal roles

Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 
L-selectin. The soluble form of L-selectin, a leukocyte-specific adhesion molecule involved in the initial rolling of leukocytes on endothelium, is present at high concentrations in normal serum (12). Although the observed concentrations are insufficient for a complete inhibition of the interaction of L-selectin-expressing activated leukocytes to endothelium, which requires 5- to 10-fold higher levels, they are considered to be high enough to cause a significant inhibition that may be effective at sites of subacute inflammation. Besides this systemic effect of L-selectin shedding, the inhibition of shedding of L-selectin from leukocytes was shown to alter the rolling behavior of leukocytes over activated endothelium and to enhance leukocyte recruitment (9). In addition, a number of anti-inflammatory drugs induce L-selectin shedding and, consequently, reduce leukocyte adhesiveness. These findings indicate that constitutive shedding of L-selectin may be considered a physiological anti-inflammatory process.

Endothelial adhesion molecules. In many inflammatory diseases, such as atherosclerosis or rheumatoid arthritis, elevated levels of soluble endothelial adhesion molecules, including E- and P-selectin, ICAM-1, and VCAM-1, have been detected in the circulating blood. Thus, in contrast to L-selectin, a positive correlation exists between shedding of these endothelial adhesion molecules for leukocytes and inflammation. The plasma levels of the endothelium-derived soluble adhesion molecules are lower (between 5- and 50-fold) than soluble L-selectin concentrations, and it is probable that these levels are not sufficient for a systemic inhibitory effect on leukocyte adhesion to endothelium. Rather, the fact that their concentration increases between two- and fivefold in coronary artery disease indicates that their cleavage from the cell surface may be linked to increased leukocyte recruitment. Since leukocyte recruitment involves a sequence of adhesive events that are mediated by different classes of adhesion molecules, shedding may facilitate a rapid switch from one class to a second class of these adhesive interactions. Some evidence for this second hypothesis stems from studies on the upregulation of L-selectin shedding by chemoattractants that stimulate leukocyte diapedesis (9). These findings also indicate that both constitutive and inducible shedding mechanisms exist that serve different functions. Besides adhesion molecules, the shedding of other classes of transmembrane molecules such as cytokines and cytokine receptors is also of importance in the regulation of inflammation in vascular disease.

	Shedding of cytokine precursors and receptors

Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 
Other classes of transmembrane proteins that are important for vascular biology are cytokines and their receptors. Tumor necrosis factor (TNF) is an inflammatory mediator that is expressed on the cell surface as a transmembrane pro-protein. TNF shedding is considered an activation step, although some capacity as an inflammatory activator has also been described for membrane bound pro-TNF. Like pro-TNF, the receptor TNFRII (p75) can also be shed. Interestingly, shedding can be induced by TNF itself, suggesting that it may serve as a rapid mechanism for downregulation of the TNF receptor signaling system following TNF-mediated binding and activation (6). The fine tuning of shedding of cytokine proforms and receptors can, therefore, be considered an important pathway in the regulation of cellular functions.

The enzymes responsible for shedding of transmembrane molecules were only discovered recently and belong to a novel family of proteins called a disintegrin and metalloproteases (ADAMs). They form a large gene family with a highly conserved domain structure but diverse biological functions.

	Regulated release of cell surface molecules by novel metalloproteases of the ADAM family

Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 
ADAMs are a novel family of transmembrane molecules that have been implicated in cell adhesion and fusion as well as in the proteolytic release of cell surface molecules, which is also called shedding. Thirty members of this protein family have been identified to date (see http://www.gene.ucl.ac.uk/users/hester/metallo.htm; Refs. 1 and 13). They all share a common domain structure (Fig. 1). They consist of a prodomain, a metalloprotease domain, a disintegrin domain, a cysteine-rich domain, an epidermal growth factor (EGF)-like domain, a transmembrane domain, and a cytoplasmic domain. About half of the ADAM family members have a metalloprotease consensus sequence, indicating that they may exhibit proteolytic activity.

View larger version (34K): [in this window] [in a new window]   FIGURE 1. Systemic and focal roles of adhesion molecule shedding by a disintegrin and metalloproteases (ADAMs) in atherosclerosis. A: constitutive shedding of L-selectin from leukocytes generates soluble antagonists that inhibit adhesion of leukocytes to endothelium and thus leukocyte influx, preventing atherosclerosis. The inset shows an enlargement of an ADAM cleaving a selectin on an endothelial cell. B: in atherosclerosis, leukocytes are recruited to sites of injury in the vessel wall in a process involving multiple adhesive steps. Elevated levels of adhesion molecules such as E-selectin of vascular cell adhesion molecule indicate that regulated focal shedding is required to allow leukocytes to attach and transmigrate, probably by mediating the switch between different types of adhesion.

"...ADAMs...have also been shown to mediate cell adhesion to cells or matrix components."

	Enzymatic roles of ADAMs

Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 
The functional implications of cell surface protein shedding by metalloproteases such as ADAMs are as diverse as are the substrates. Several cytokines and growth factors exist as membrane-bound proforms that can be "activated" by proteolysis and released from the cell surface into the interstitium. ADAMs have also been shown to play a role in shedding of receptors for cytokines and growth factors. Although studies of the detailed effects of receptor shedding on cellular functions are still missing, this process is expected to constitute an alternative pathway for receptor downregulation with both a paracrine and an autocrine mode of action, since the released extracellular domains may act as natural antagonists for binding of the respective cytokines and growth factors to their receptors (7).

	Physiological and pathophysiological functions

Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 
Although little is known about the physiological and pathophysiological roles of most members of the ADAM family, evidence exists for a wide diversity of functions of these novel molecules in development and disease. The TNF-converting enzyme TACE (ADAM17) was the first member of this family for which a role in shedding was demonstrated. TACE has been implicated in the release of multiple transmembrane molecules, including TNF, TNFRII (p75), and L-selectin (1). The analysis of mice in which the metalloprotease of TACE was inactivated by targeted deletion provided evidence for a role of TACE and the process of cell surface molecule shedding in development. Defects were found in eye, hair follicle, and skin development. In addition, the TACE metalloprotease-deficient mice suffered from pulmonary hypoplasia, which could be reversed by the addition of soluble TNF or EGF ex vivo, and exhibited delayed blood vessel formation, with a reduction in platelet-endothelial cell adhesion molecule (PECAM-1)-positive endothelial cells, an indication that TACE is essential for the development of the vascular network in lungs. The fact that neither TNF- nor TNF receptor-null mice exhibit any defect in lung morphogenesis indicates that TACE-mediated processing of membrane anchored molecules other than TNF may be responsible for the developmental defects in these mice (15).

The importance of ADAMs is based not only on their enzymatic functions. They have also been shown to mediate cell adhesion to cells or matrix components.

	ADAMs also function as adhesion molecules

Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 
The disintegrin and cysteine-rich domains of ADAMs are structurally related to long-chain snake venom disintegrins (LCSVD). LCSVD have been shown to inhibit interactions of non-RGD-binding integrins, such as ₂ß₁, with their ligands (e.g., collagen). In in vitro assays, several ADAMs have been shown to mediate integrin binding and thus cell adhesion. An adhesive capacity has also been demonstrated for the cysteine-rich domain of ADAM12, which can interact with heparan sulfate proteoglycans (HSPGs), which exist as extracellular matrix components or membrane-attached cell surface molecules. In addition to this direct function in mediating adhesion, the proteolytic ADAMs may also be involved in cleavage of cell adhesion molecules. A more detailed discussion of this aspect will follow in the next paragraph. Consequently, about half of the ADAM family members may serve a dual function, namely mediating cell adhesion through their disintegrin and cysteine-rich domains and inhibiting certain adhesive interactions by cleaving the respective cell adhesion molecules via their metalloprotease (13).

	Endothelial-leukocyte adhesion

Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 
ADAMs have been identified in different types of tissues and cells. A detailed analysis of the expression of different ADAMs in vascular cells has not been performed yet. However, four ADAMs [ADAM1, -12, -15 and -17 (TACE)] have been identified in smooth muscle cells, and ADAM15 and -17 are also expressed in endothelial cells (5). All of these are putative metalloproteases and, on the basis of results found in different systems, may play roles in the regulation of smooth muscle and endothelial functions via both their proteolytic and adhesive properties.

ADAMs consist of adhesive domains that are related to a class of snake venom integrin antagonists, the disintegrins. Similar to their snake venom relatives, ADAMs have been shown to interact with different types of integrins. Among the ADAMs expressed in vascular cells, human ADAM15, which is the only ADAM with an RGD tripeptide, has been proposed to be involved in endothelial-leukocyte or endothelial-tumor adhesion by virtue of its ability to bind to the classic RGD-binding integrins ₅ß₁ and _vß₃ (10,14). In addition, non-RGD-type interactions with integrin ₉ß₁ have also been demonstrated for ADAM15 (2).

	Smooth muscle cells

Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 
ADAMs may also be involved in non-integrin-mediated interactions in the vessel wall. ADAM12, which is expressed in cultured human smooth muscle cells, has been shown to interact with HSPGs through its cysteine-rich domain (8). Notably, ADAM12 exists both as a membrane-bound form and an alternatively spliced secreted form. Secreted ADAM12 may be incorporated into the matrix and mediate cell adhesion by binding to integrins or cell surface HSPGs, such as syndecans, or may interfere with integrin-mediated cell adhesion to matrix, similar to thrombospondins. Consequently, ADAMs may be involved in cell-cell and cell-matrix types of interactions in the vessel wall.

Given that many substrates and ligands of ADAMs mediate different steps in lesion formation in atherosclerosis, the question arises as to whether ADAMs also play critical roles in the development of this vascular disease.

	Do ADAMs play a role in the pathophysiology of atherosclerosis?

Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 
The shedding of cell surface molecules by ADAMs is emerging as a novel and critical pathway that regulates cellular function. A number of substrates for ADAMs play important roles in the development of lesions in atherosclerosis, such as adhesion molecules, cytokines, growth factors, and their receptors. The fact that one member of the ADAM family, ADAM15, was shown to be upregulated in lesions of atherosclerosis suggests that ADAMs also participate in lesion formation. The identification of ADAMs that play a role in lesions, and of the mechanisms of cleavage of different substrates and their contribution to lesion formation, may allow the definition of novel leads for the development of therapeutic intervention.

	Glossary

Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 
ICAM-1: a member of the immunoglobulin superfamily of adhesion molecules, it is expressed on endothelial and mesenchymal cells following activation. ICAM-1 participates in tight leukocyte adhesion and spreading on endothelial cells by interacting with ß₂-integrins on leukocytes.

VCAM-1: another immunoglobulin superfamily member, VCAM-1 has been shown to be upregulated by endothelial cells in areas of the vasculature prone to lesion formation in models for atherosclerosis. VCAM-1 mediates tight binding and spreading of activated leukocytes by binding to leukocyte ₄ß₁-integrin

L-selectin: this leukocyte adhesion molecule is involved in the initial interaction between leukocytes and the activated endothelium called rolling. L-selectin also acts as a homing receptor for targeting of leukocytes to the lymphatic tissue.

E- and P-selectin: endothelial and platelet selectins are stored intracellularly in endothelial cells and translocate to the cell surface when cells are activated. They mediate the initial rolling of leukocytes over the activated endothelium.

ADAM: a family of proteins that have been implicated in shedding and adhesion. Some members of this family include:

1) ADAM15, also known as MDC 15 or metargidin. Human ADAM 15 is the only known member of this protein family with an RGD peptide in the putative integrin binding site. It has been shown to interact in an RGD-dependent manner, as well as by an RGD-independent mechanism with diverse integrins.

2) ADAM17, also known as TACE, was originally identified as an activity capable of converting membrane-bound pro-TNF to soluble TNF.

Integrins: also called very late antigens (VLAs), these are heterodimeric adhesion molecules consisting of an and a ß chain, which are upregulated very late following T cell activation and which, on all adhesive cells, mediate cell-matrix or cell-cell interactions. Integrins control various cellular functions, such as cell proliferation, migration, and survival.

RGD: a tripeptide consisting of an arginine-glycine-aspartic acid (in this sequence) that, when presented in the proper conformation, interacts with specific integrins (_vß₃, ₅ß₁, _IIbß₃).

Shedding: this is the regulated extracellular enzymatic cleavage of proteins that are attached to the cell surface, leading to the generation of a soluble extracellular fragment.

LCSVD: these soluble molecules found in snake venoms have the property of interfering with platelet aggregation by preventing the interaction of non-RGD-dependent integrins with their prothrombotic ligands (e.g., collagen).

	Acknowledgments

 
I am grateful to Christian Bauer for his many helpful suggestions.

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Top Introduction Leukocyte recruitment and... Adhesion molecule shedding from... Shedding of cytokine precursors... Regulated release of cell... Enzymatic roles of ADAMs Physiological and... ADAMs also function as... Endothelial-leukocyte adhesion Smooth muscle cells Do ADAMs play a... Glossary References

 

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