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Biomedical subjects

M D Pierschbacher

Publications and source records attributed to M D Pierschbacher.

At least 19 recordsLinked to original sources
PubMed2000

Integrin alpha(IIb)beta(3) inhibitor preserves microvascular patency in experimental acute focal cerebral ischemia.

BACKGROUND AND PURPOSE: Platelets become activated and accumulate in brain microvessels of the ischemic microvascular bed after experimental focal cerebral ischemia. The binding of glycoprotein IIb/IIIa (integrin alpha(IIb)beta(3)) on platelets to fibrinogen is the terminal step in platelet adhesion and aggregation. This study tests the hypothesis that inhibition of platelet-fibrin(ogen) interactions may prevent microvascular occlusion after experimental middle cerebral artery occlusion (MCA:O). METHODS: TP9201 is a novel Arg-Gly-Asp (RGD)-containing integrin alpha(IIb)beta(3) inhibitor. Microvascular patency after 3-hour MCA:O and 1-hour reperfusion within the ischemic and nonischemic basal ganglia was compared in adolescent male baboons who received high-dose TP9201 (group A: IC(80) in heparin, n=4), low-dose TP9201 (group B: IC(30) in heparin, n=4), or no treatment (group C: n=4) before MCA:O. RESULTS: After MCA:O, microvascular patency decreased significantly in group C. However, in the ischemic zones of groups A and B compared with group C, patencies were significantly greater in the 4.0- to 7. 5-microm-diameter (capillary) and 7.5- to 30.0-microm-diameter vessels (2P<0.05). A dose-dependent increase in hemorrhagic transformation was seen in group A (3 of 4 animals) compared with group B (1 of 4 animals), and no hemorrhage was visible in group C (chi(2) analysis for trend, P<0.05). CONCLUSIONS: Platelet activation contributes significantly to ischemic microvascular occlusion. Occlusion formation may be prevented by this RGD-integrin alpha(IIb)beta(3) inhibitor at a dose that does not produce clinically significant parenchymal hemorrhage. The effect of microvascular patency on neuron recovery can now be tested.

Animals↗
PubMed1997

Antifibrotic effect of decorin in a bleomycin hamster model of lung fibrosis.

We reported previously that treatment with antibody to transforming growth factor-beta (TGF-beta) caused a marked attenuation of bleomycin (BL)-induced lung fibrosis (LF) in mice. Decorin (DC), a proteoglycan, binds TGF-beta and thereby down-regulates all of its biological activities. In the present study, we evaluated the antifibrotic potential of DC in a three-dose BL-hamster model of lung fibrosis. Hamsters were placed in the following groups: (1) saline (SA) + phosphate-buffered saline (PBS) (SA + PBS); (2) SA + DC; (3) BL + PBS; and (4) BL + DC. Under pentobarbital anesthesia, SA (4 mL/kg) or BL was instilled intratracheally in three consecutive doses (2.5, 2.0, 1.5 units/kg/4 mL) at weekly intervals. DC (1 mg/mL) or PBS was instilled intratracheally in 0.4 mL/hamster on days 3 and 5 following instillation of each dose of SA or BL. In week 4, hamsters received three doses of either DC or PBS every other day. The hamsters were killed at 30 days following the first instillation, and their lungs were appropriately processed. Lung hydroxyproline levels in SA + PBS, SA + DC, BL + PBS, and BL + DC groups were 965, 829, 1854, and 1387 microg/lung, respectively. Prolyl hydroxylase activities were 103, 289, and 193% of SA + PBS control in SA + DC, BL + PBS, and BL + DC groups, respectively. The myeloperoxidase activities in the corresponding groups were 222, 890, and 274% of control (0.525 units/lung). Intratracheal instillation of BL caused significant increases in these biochemical markers, and instillation of DC diminished these increases in the BL + DC group. DC treatment also caused a significant reduction in the infiltration of neutrophils in the bronchoalveolar lavage fluid (BALF) of hamsters in the BL + DC group. However, DC treatment had little effect on BL-induced increases in lung superoxide dismutase activity and lipid peroxidation and leakage of plasma proteins in the BALF of the BL + DC group. Hamsters in the BL + PBS group showed severe multifocal fibrosis and accumulation of mononuclear inflammatory cells and granulocytes. In contrast, hamsters in the BL + DC group showed mild multifocal septal thickening with aggregations of mononuclear inflammatory cells. Hamsters in both control groups (SA + PBS and SA + DC) showed normal lung structure. Frozen lung sections following immunohistochemical staining revealed an intense staining for EDA-fibronectin and collagen type I in the BL + PBS group as compared with all other groups. It was concluded that DC potentially offers a novel pharmacological intervention that may be useful in treating pulmonary fibrosis.

Animals↗
PubMed1997

Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release.

Decorin (DCN) is a ubiquitous proteoglycan comprised of a core protein attached to a single dermatan/chondroitin sulphate glycosaminoglycan chain. It may play a role in regulation of collagen fibrillogenesis and function as a reservoir of transforming growth factor beta (TGF-beta) in the extracellular milieu. We have examined the susceptibility of DCN to five different matrix metalloproteinases (MMPs): MMP-1 (tissue collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin 1), MMP-7 (matrilysin) and MMP-9 (gelatinase B). MMP-2 and MMP-3 digest DCN into seven major fragments in a similar pattern. The N-terminal sequence of the two fragments generated by MMP-2 and MMP-3 is Leu211-Lys-Gly-Leu-Asn, but that of the others is Asp1-Glu-Ala-Ser-Gly. MMP-7 cleaves DCN into three major fragments which have the N-termini Asp1-Glu-Ala-Ser-Gly, Glu2-Ala-Ser-Gly-Ile and Leu244-His-Leu-Asp-Asn. Activities of MMP-1 and MMP-9 against DCN are negligible. The values of Km for the MMPs capable of degrading DCN are very similar (10-12 microM), but the kcat/Km value for MMP-7 (30.5 microM-1.h-1) is 4.5-fold higher than those for MMP-2 and MMP-3. Incubation of a DCN-TGF-beta1 complex with MMP-2, -3 or -7 results in release of TGF-beta1 from the complex. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.

Amino Acid Sequence↗
PubMed1997

Enhancement of cell interactions with collagen/glycosaminoglycan matrices by RGD derivatization.

The interaction of three cell types important to the wound repair process with collagen/glycosaminoglycan (GAG) dermal regeneration matrices covalently modified with an Arg-Gly-Asp (RGD)-containing peptide was characterized. Function-blocking monoclonal antibodies directed against various integrin subunits were used to demonstrate that human fibroblasts attached to the unmodified matrix through the integrin, alpha2beta1. Human endothelial cells and human keratinocytes, however, attached minimally to the unmodified matrix. After modification of the collagen/GAG matrix with RGD-containing peptide, endothelial cells and keratinocytes attached and spread well on the matrix. This attachment was RGD dependent as evidenced by essentially complete inhibition with competing soluble peptide. In terms of overall cell number, fibroblast cell attachment remained unchanged on the RGD peptide-modified matrix compared to the unmodified material. Antibody and peptide inhibition studies demonstrate, however, that attachment to the modified matrix was mediated by both alpha2beta1 and RGD-binding integrins. We have successfully introduced a specific RGD receptor-mediated attachment site on collagen/GAG dermal regeneration matrices, resulting in enhanced cell interaction of important wound healing cell types. This modification could have important implications for the performance of these matrices in promoting dermal regeneration.

Antibodies, Monoclonal↗
PubMed1995

Concept and progress in the development of RGD-containing peptide pharmaceuticals.

The cell adhesion domain, arginine-glycine-aspartic acid (RGD), has been incorporated into synthetic peptides to perform either of two modes of drug action, antagonist or agonist. Short, conformationally constrained peptides have been developed as antagonists for the platelet membrane glycoprotein complex, the integrin alpha IIb beta 3, using cell-based and integrin-based assays. In combination with a comparative molecular modeling study, these results have helped identify common conformational elements in the pharmacophore of this class of molecules. Peptides are presented that are highly potent, integrin specific, and that possess reduced pharmacological side effects. Also presented is the development of a peptide that modifies, noncovalently, the surfaces of a wide variety of synthetic materials used in medical implants. The agonist activity of [corrected] this molecule is evident from its ability to stimulate cell attachment on these surfaces. This is shown to translate into an in vivo activity of faster and more complete tissue integration, and a reduction in foreign body response.

Amino Acid Sequence↗
PubMed1995

Changes in the concentrations of extracellular Mg++ and Ca++ down-regulate E-cadherin and up-regulate alpha 2 beta 1 integrin function, activating keratinocyte migration on type I collagen.

We have demonstrated recently that shifts in the concentrations of extracellular Mg++ and Ca++ occur during cutaneous injury in vivo. These shifts correlate well with the timing of migration of various cell types involved in wound healing, including keratinocytes. In the present study, we examined the potential of such cation shifts to activate the keratinocyte migratory phenotype. In modified Boyden chamber migration assays, alpha 2 beta 1 integrin-mediated migration of human keratinocytes (HaCaT) on type I collagen was supported by Mg++ but not by Ca++ alone. Migration could be increased up to twofold, however, by using both cations in combination, as long as the Mg++ concentration was in the optimal range for migration in Mg++ only (1-3 mM) and Ca++ was present at concentrations of approximately 0.1-1 mM. Further examination of this divalent-cation-induced migratory keratinocyte phenotype demonstrated that, as Mg++ is elevated and Ca++ is reduced, mature E-cadherin and cell-cell contacts are reduced and the alpha 2 beta 1 integrin is redistributed from cell-cell contacts to the periphery. These in vitro observations corroborate what occurs in vivo at the keratinocyte migrating front during wound healing. Together these data suggest that changes in the concentrations of extracellular Mg++ and Ca++ can regulate the competitive interplay between Ca(++)-dependent E-cadherin-mediated and Mg(++)-dependent alpha 2 beta 1-integrin-mediated adhesion, promoting the development of an activated keratinocyte phenotype.

Antigens, CD↗
PubMed1995

Shifts in the concentrations of magnesium and calcium in early porcine and rat wound fluids activate the cell migratory response.

Accruing evidence indicates that the levels of extracellular Mg2+ and Ca2+ can have a distinct impact on the adhesive and migratory activities of many cell types. The physiological relevance of these observations, however, has remained largely unexplored. In the present study, wound fluids collected throughout the early stages of cutaneous wound repair were examined for possible Mg2+ and Ca2+ fluctuations. Early in the process, when cell migration into the wound site is initiated, Mg2+ is elevated and Ca2+ is reduced (Mg2+:Ca2+ = 1). As wound healing progresses, wound fluid concentrations of Mg2+ and Ca2+ begin to return to normal plasma levels (Mg2+:Ca2+ = 0.4). When macrophages, keratinocytes, fibroblasts, and endothelial cells were exposed to dialyzed wound fluid, the migration stimulated by undialyzed wound fluid was lost. Addition back to dialyzed wound fluid of 24 h, postinjury concentrations of Mg2+ and Ca2+ restored all migratory stimulus. This observed migration is approximately twofold greater than when normal plasma Mg2+ and Ca2+ concentrations are present. Changes in the levels of Mg2+ and Ca2+ in wound fluid occur during the same period that inflammatory cells, keratinocytes, fibroblasts, and neovasculature have been shown to migrate during wound healing in vivo. Together, these data suggest that the impact of these changes on integrins and E-cadherin may play a direct role in the activation and maintenance of the migratory phenotypes of the cells involved in the wound healing process.

Animals↗
PubMed1994

Design and synthesis of novel cyclic RGD-containing peptides as highly potent and selective integrin alpha IIb beta 3 antagonists.

Utilizing conformational constraints in conjunction with various structural considerations, we have synthesized a series of cyclic disulfide peptides that are highly potent and selective antagonists for the platelet integrin alpha IIb beta 3 (GPIIb/IIIa). The affinities of the peptides for alpha IIb beta 3 were determined by platelet aggregation assays and an alpha IIb beta 3 ELISA. Their affinities for alpha 5 beta 1 and alpha v beta 5 integrins were also determined in respective ELISA assays. Structure-activity relationship studies suggest that R-G-D-Ar-R (Ar = hydrophobic residue) is the essential pharmacophore that is responsible for their high alpha IIb beta 3 binding affinity, very high selectivity, and distinct biological properties. One of these analogues, TP9201, has been shown to inhibit platelet-mediated thrombus formation without associated prolongation of template bleeding time. The arginine residue adjacent the carboxy terminus of the R-G-D-Ar sequence could function as the biological effector element that determines this distinct and unexpected biological property.

Amino Acid Sequence↗
PubMed1994

Manipulation of cellular interactions with biomaterials toward a therapeutic outcome: a perspective.

Manipulation of the wound healing process and the manner in which tissues interact with inert biomaterials were both made possible with the discovery of arginine-glycine-aspartic (RGD) acid as a major cell recognition signal in the extracellular matrix. Whether promoting cell adhesion or selectively inhibiting cell-cell aggregation mediated by integrin cell surface receptors, RGD-containing peptides can be rationally designed to incorporate both stability and integrin specificity. Synthetic peptides containing this sequence have been linked to biodegradable biopolymers and introduced for the enhancement of dermal and corneal would healing. By accelerating the healing reaction using RGD-containing peptides, the quality of regenerated tissue seems to be improved, the extent of fibrosis restricted, and the risk of microbial infection may be reduced. Controlling the degree of fibrosis that often accompanies the healing of wounds and the reaction of tissue to foreign materials can also be achieved by natural antagonists of fibrogenic activity of TGF-beta animal models of kidney fibrosis. These advances in the biotechnology of wound healing and tissue regeneration eventually will have an overall impact on the quality of health care.

Amino Acid Sequence↗
PubMed1994

Selective alpha IIb beta 3 receptor blockage with peptide TP9201 prevents platelet uptake on Dacron vascular grafts without significant effect on bleeding time.

Synthetic vascular prostheses lack the uniquely low thrombogenicity provided by the endothelial cell lining of autogenous saphenous vein or artery grafts. The thrombogenic nature of the synthetic graft surface becomes a major determinant of early prosthetic graft patency. We demonstrate in a baboon ex vivo synthetic graft model that modification of the host's platelet interaction with the graft surface results in inhibition of platelet thrombus formation and thereby, a possible enhancement of early prosthetic graft patency. This was achieved by selective blockage of the platelet alpha IIb beta 3 receptor by the arginine-glycine-aspartic acid-containing synthetic peptide TP9201. Platelet thrombus formation on a Dacron graft indicated by accumulation of indium III-oxine-labeled autologous platelets was measured by gamma camera imaging. After 60 minutes of circulation, TP9201 at a bolus of 125 micrograms/kg; infusion of 3 micrograms/kg/min, bolus of 190 micrograms/kg; infusion of 5 micrograms/kg/min, bolus of 250 micrograms/kg; infusion of 6 micrograms/kg/min, and bolus of 500 micrograms/kg; infusion of 12 micrograms/kg/min decreased platelet uptake on the graft to 50%, 40%, 30%, and 10% of control uptake, respectively. Forelimb template bleeding times were not found to be significantly prolonged at doses that effectively inhibit ex vivo platelet aggregation. As a result of drug treatment, no changes in hemodynamic parameters or hematologic profile, including platelet number and clotting time, were observed. We demonstrate here that the arginine-glycine-aspartic acid-containing peptide TP9201, which competitively inhibits the alpha IIb beta 3 integrin-fibrinogen interaction, significantly decreased the accumulation of platelets on a Dacron vascular graft. Molecules like peptide TP9201, because of its unique activity profile, may represent a superior approach to the control of platelet accumulation on thrombogenic surfaces.

Animals↗
PubMed1994

Inhibition of thrombosis by a selective fibrinogen receptor antagonist without effect on bleeding time.

Membrane glycoprotein alpha IIb beta 3 on platelets plays a pivotal role in hemostasis by mediating RGD-(arginine-glycine-aspartic acid)-dependent platelet adhesion and aggregation. Antagonists of alpha IIb beta 3 ligand binding function, such as antibodies, snake venom peptides, or synthetic RGD-containing peptides can completely inhibit platelet aggregation in vitro and cause significant prolongation of bleeding times when injected into experimental animals. The in vitro and in vivo properties of an alpha IIb beta 3 specific RGD-containing peptide 2G (G(Pen)GHRGDLRCA) were compared to two non-specific RGD-containing peptides 1N (G(Pen)GRGDTPCA) and 2H (GRGDSPDG). All three peptides have similar IC50 values in human platelet aggregation (14-22 microM) and ELISA-based alpha IIb beta 3 receptor assays (0.2-0.3 microM) but show different inhibitory activity (IC50 values) in the alpha v beta 5 (2G = 10 microM; 1N = 0.06 microM; 2H = 0.05 microM) and alpha 5 beta 1 receptor assays (2G = 8.3 microM; 1N = 0.06 microM; 2H = 0.04). The alpha IIb beta 3 specific peptide 2G had no effect on monolayers of human saphenous vein endothelial cells while 1N and 2H caused many cells to detach and contract. Peptides 2G and 1N inhibited ADP-stimulated ex vivo platelet aggregation in dogs in a dose dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

A 30 kD sulfated extracellular matrix protein immunologically crossreactive with vitronectin.

In this study we describe a human sulfated 30 kD protein (sp30) that is recognized by a monoclonal antibody raised against human vitronectin (mAb 8E6). Another monoclonal antibody raised against human vitronectin, mAb MaSp, and a polyclonal antiserum against vitronectin did not react detectably with sp30. Sp30, unlike vitronectin, is synthesized by a variety of non-hepatic human cell lines in culture, including cells of lymphoid origin. It is synthesized in sulfated form as indicated by metabolic labeling of MG-63 human osteosarcoma cells with 35SO4. Sp30 is an extracellular matrix protein as indicated by its association with the matrix of MG-63 cells after removal of the cells with EDTA and its fibrillar pattern by immunofluorescence of non-permeabilized confluent MG-63 cell monolayers detected with mAb 8E6. This antibody also stained short fibrils in human embryonic tissue. This pattern was distinct from the fainter diffuse staining obtained with mAb MaSp and the polyclonal antiserum to vitronectin, suggesting that the 8E6 staining in embryonic tissues was mostly due to sp30 rather than vitronectin. A polyclonal antiserum against bovine microfibril associated glycoprotein (MAGP) precipitated a [35SO4]-30 kD protein from [35SO4]-labeled MG-63 medium that co-migrated with a band precipitated by mAb 8E6. Double-labeling immunofluorescence studies of embryonic tissues showed an identical distribution of anti-bovine MAGP antiserum and mAb 8E6 staining. These data indicate that sp30 is the human homolog of bovine MAGP. Distinction between sp30 and vitronectin will be important in ascertaining the localization and function of both proteins. The findings that sp30 is sulfated and synthesized and secreted by a variety of cells in culture should aid in defining its role in microfibrillogenesis. That sp30 is secreted by cells of lymphoid origin suggests that it might also have a heretofore unsuspected role in immune responses.

Animals↗
PubMed1993

A novel integrin specificity exemplified by binding of the alpha v beta 5 integrin to the basic domain of the HIV Tat protein and vitronectin.

Several studies have addressed the interaction of the HIV Tat protein with the cell surface. Our analysis of the cell attachment-promoting activity of Tat and peptides derived from it revealed that the basic domain of Tat, not the arg-gly-asp (RGD) sequence, is required for cell attachment to Tat. Affinity chromatography with Tat peptides and immunoprecipitation with various anti-integrin antibodies suggest that the vitronectin-binding integrin, alpha v beta 5, is the cell surface protein that binds to the basic domain of Tat. The Tat basic domain contains the sequence RKKRRQRRR. A related sequence, KKQRFRHRNRKG, present in the heparin-binding domain of an alpha v beta 5 ligand, vitronectin, also bound alpha v beta 5 in affinity chromatography and, in combination with an RGD peptide, was an inhibitor of cell attachment to vitronectin. The alpha v beta 5 interaction with these peptides was not solely due to high content of basic amino acids in the ligand sequences; alpha v beta 5 did not bind substantially to peptides consisting entirely of arginine or lysine, whereas a beta 1 integrin did bind to these peptides. The interaction of alpha v beta 5 with Tat is atypical for integrins in that the binding to Tat is divalent cation independent, whereas the binding of the same integrin to an RGD-containing peptide or to vitronectin requires divalent cations. These data define an auxiliary integrin binding specificity for basic amino acid sequences. These basic domain binding sites may function synergistically with the binding sites that recognize RGD or equivalent sequences.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Inhibition of coronary artery reocclusion after thrombolysis with an RGD-containing peptide with no significant effect on bleeding time.

BACKGROUND: A synthetic RGD-containing cyclic peptide, TP9201, specific for the platelet alpha IIb beta 3 receptor complex, was tested for its ability to accelerate thrombolysis and prevent reocclusion in experimentally induced coronary artery thrombosis. METHODS: Anesthetized, open-chest dogs with occlusive thrombi received tissue plasminogen activator with TP9201 (113 micrograms/kg bolus; 2.7 micrograms/kg/min infusion, n = 7) or saline control (n = 9). RESULTS: A 2.8-fold increase in the duration of vessel patency from 52.7 +/- 63.7 min to 149.1 +/- 63.7 min (P < 0.05) was observed with TP9201 treatment. The mean duration of vessel occlusion was reduced 2.4-fold from 172.4 +/- 81.1 min to 71.7 +/- 63.7 min (P < 0.05). Administration of TP9201 reduced the mean time to lysis from 76.6 +/- 42.9 min to 54.4 +/- 42.9 min, but thrombolysis was not significantly accelerated. Persistent patency was observed in four out of seven of the treated dogs compared with none of the nine in the control group (P < 0.05). Administration of TP9201 inhibited ex-vivo platelet aggregation stimulated by ADP (30 microM) or collagen (10 micrograms/ml). No thrombocytopenia or changes in hemodynamic parameters were observed in the treated group compared with the control group. Peptide TP9201 had no effect on bleeding time and the inhibitory effect on ex-vivo platelet aggregation was rapid and reversible. The pharmacodynamic half-life of TP9201 was approximately 1 h with ex-vivo platelet activity returning to baseline within 2 h of discontinuation of treatment. CONCLUSIONS: TP9201 may be an effective therapy for the prevention of re-thrombosis after thrombolytic therapy without adversely affecting hemostasis.

Animals↗
PubMed1992

Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease.

The central pathological feature of human kidney disease that leads to kidney failure is the accumulation of extracellular matrix in glomeruli. Overexpression of transforming growth factor-beta (TGF-beta) underlies the accumulation of pathological matrix in experimental glomerulonephritis. Administration of an antibody raised against TGF-beta to glomerulonephritic rats suppresses glomerular matrix production and prevents matrix accumulation in the injured glomeruli. One of the matrix components induced by TGF-beta, the proteoglycan decorin, can bind TGF-beta and neutralize its biological activity, so decorin may be a natural regulator of TGF-beta (refs 3, 4). We tested whether decorin could antagonize the action of TGF-beta in vivo using the experimental glomerulonephritis model. We report here that administration of decorin inhibits the increased production of extracellular matrix and attenuates manifestations of disease, confirming our hypothesis. On the basis of our results, decorin may eventually prove to be clinically useful in diseases associated with overproduction of TGF-beta.

Animals↗
PubMed1992

Regulation of alpha 2 beta 1-mediated fibroblast migration on type I collagen by shifts in the concentrations of extracellular Mg2+ and Ca2+.

Extracellular Ca2+ can reverse the Mg(2+)-dependent, alpha 2 beta 1-mediated adhesion of WI38 human fibroblasts to type I collagen substrates. Affinity chromatography data also demonstrate that Ca2+ can specifically elute the fibroblast alpha 2 beta 1 integrin bound to type I collagen-Sepharose in Mg2+. In modified Boyden chamber migration assays, Mg2+ alone supports the alpha 2 beta 1-mediated migration of fibroblasts on type I collagen substrates, while Ca2+ does not. However, a twofold enhancement in migration was observed when combinations of the two cations were used, with optimal migration observed when the Mg2+/Ca2+ ratio was higher than one. Inhibitory mAbs directed against various integrin subunits demonstrate that these observed cation effects appear to be mediated primarily by alpha 2 beta 1. These data, together with reports that under certain physiological conditions significant fluctuations in the concentrations of extracellular Ca2+ and Mg2+ can take place in vivo, suggest that the ratio between these two cations is involved in the up- and downregulation of integrin function, and thus, may influence cell migratory behavior.

Amino Acid Sequence↗