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Biomedical subjects

J A Ware

Publications and source records attributed to J A Ware.

At least 19 recordsLinked to original sources
PubMed2001

The thromboxane A2 receptor activates mitogen-activated protein kinase via protein kinase C-dependent Gi coupling and Src-dependent phosphorylation of the epidermal growth factor receptor.

The mitogen-activated protein kinase signaling cascade is used by many G protein-coupled receptors to initiate functional events. In this study, activation of the Gq/G11-coupled thromboxane A2 (TxA2) receptor (TP) by the TxA2 mimetic IBOP in ECV304 cells was found to induce extracellular regulated kinase (ERK) phosphorylation and tyrosine phosphorylation of the epidermal growth factor receptor (EGFR), which were inhibited by the TP antagonist SQ29548, the EGFR kinase inhibitor AG1478, the Src family kinase inhibitor PP1, the Gi/o protein inhibitor pertussis toxin (PTX), or the protein kinase C (PKC) inhibitor calphostin C. TP activation also increased Src kinase activity, which was blocked by PTX, PP1, and calphostin C, but not by AG1478, indicating that Src activation occurs before phosphorylation of EGFR. Blockade of Src activity by expression of dominant negative mutant of Src inhibits mitogen-activated protein kinase (MAPK) activation induced by TxA2. ERK activation induced by the PKC activator phorbol myristate acetate was inhibited by PTX, PP1, AG1478, and calphostin C. In contrast, activation of ERK by lysophosphatidic acid, a Gi-coupled receptor activator, was inhibited by PTX, PP1, and AG1478, but not by calphostin C. Thus, TP-stimulated ERK activation requires Gi, which in turn requires PKC activation. Immunoprecipitation of Galphai showed increased association of Galphai with TPalpha following PKC activation. In conclusion, TPalpha is directly coupled to the Gi protein by a PKC-regulated mechanism; Gi coupling causes Src-dependent transactivation of the EGFR, which is the dominant pathway in TP-mediated ERK activation.

Cell Line↗
PubMed2000

Reversal of angiogenesis in vitro, induction of apoptosis, and inhibition of AKT phosphorylation in endothelial cells by thromboxane A(2).

Thromboxane A(2) (TxA(2)) causes platelet aggregation, vasoconstriction, and inhibition of endothelial cell (EC) migration and prevents vascular tube formation via its specific receptors (TP), of which there are two isoforms (TPalpha and TPbeta), both expressed in human ECs. In this study, we demonstrate that the TxA(2) mimetic IBOP increases apoptosis of human ECs and inhibits the phosphorylation of Akt kinase, an intracellular mediator required for cell survival. Treatment with IBOP destroyed EC networks formed on a basement membrane matrix in vitro. To distinguish the role of the TP isoforms, each isoform was expressed in TP-null ECs to create TPalpha and TPbeta ECs. IBOP induced apoptosis and inhibited phosphorylation of Akt kinase in both TPalpha and TPbeta. IBOP increased cAMP levels in TPalpha but not in TPbeta. Apoptosis induced by IBOP in TPalpha was not affected by either the adenylyl cyclase activator forskolin or the protein kinase A inhibitor 14-22 amide or H-89, whereas that in TPbeta was suppressed by forskolin and enhanced by the protein kinase A inhibitor 14-22 amide or H-89, suggesting that the TP isoforms differ in their signal pathways in mediating apoptosis. In conclusion, apoptosis may be the mechanism by which TxA(2)-mediated destruction of vascular structures in ECs occurs; although both TP isoforms induce apoptosis, possibly via inhibiting Akt phosphorylation, the signaling differs in each isoform, in that activation of the adenylyl cyclase pathway prevents apoptosis caused by TPbeta, but not by TPalpha, stimulation.

Adenylyl Cyclase Inhibitors↗
PubMed2000

Endothelial proliferation, migration, and differentiation are blunted by conditionally expressed protein kinase C pseudosubstrate peptides.

Peptides based on the pseudosubstrate (PS) sequence of conventional protein kinase C isoenzymes (alpha, beta, gamma) specifically inhibit PKC activity in permeabilized cells, but whether PS can be used to study the role of PKC in the proliferation or migration of intact endothelial cells (EC) and angiogenesis is unknown. Peptides based on the PKCeta pseudosubstrate (etaPS) sequence were 3.5- to 8-fold more potent in inhibiting the PKCalpha, delta, epsilon, or eta kinase activity than was the peptide based on the PKCalpha pseudosubstrate (alphaPS) sequence. Thus, etaPS was conditionally overexpressed in intact EC and compared to alphaPS. Serum-induced growth of EC expressing etaPS was significantly slower than that of control EC. etaPS EC demonstrated slower rate of serum stimulated migration than that of either control or alphaPS EC. Expression of either etaPS or alphaPS produced slower rates of PMA induced EC migration, as compared to control EC. In an in vitro three-dimensional assay in which EC organize into capillary tubules, the EC that expressed etaPS formed fewer such tubules. This study shows that pseudosubstrate inhibitors derived from PKCeta are more potent both in vitro and in vivo than one based on the conventional isoenzyme PKCalpha. These data further support a role for PKC in proliferation and migration of intact EC, and angiogenesis.

Animals↗
PubMed2000

Therapeutic angiogenesis for ischemic heart disease.

The de-novo formation of vessels (angiogenesis) and the remodelling of preexisting collateral vessels (arteriogenesis) are processes that occur naturally in ischemic heart disease. Promoting these processes by administration of various substances or other physical stimuli (therapeutic angiogenesis) may provide a future strategy for the treatment of ischemic vascular diseases. Mechanisms of angiogenesis and arteriogenesis, as well as trials of therapeutic angiogenesis in animal models and humans are reviewed.

Animals↗
PubMed1999

Inhibition of endothelial cell migration, intercellular communication, and vascular tube formation by thromboxane A(2).

The eicosanoid thromboxane A(2) (TXA(2)) is released by activated platelets, monocytes, and the vessel wall and interacts with high affinity receptors expressed in several tissues including endothelium. Whether TXA(2) might alter endothelial migration and tube formation, two determinants of angiogenesis, is unknown. Thus, we investigated the effect of the TXA(2) mimetic [1S-(1alpha, 2beta(5Z),3alpha(1E,3R), 4alpha]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-o xab icyclo- [2.2.1]heptan-2-yl]-5'-heptenoic acid (IBOP) on human endothelial cell (HEC) migration and angiogenesis in vitro. IBOP stimulation inhibited HEC migration by 50% and in vitro capillary formation by 75%. These effects of IBOP were time- and concentration-dependent with an IC(50) of 25 nM. IBOP did not affect integrin expression or cytoskeletal morphology of HEC. Since gap junction-mediated intercellular communication increases in migrating HEC, we determined whether IBOP might inhibit coupling or connexin expression in HEC. IBOP reduced the passage of microinjected dyes between HEC by 50%, and the effects of IBOP on migration and tube formation were mimicked by the gap junction inhibitor 18beta-glycyrrhetinic acid (1 microM) with a similar time course and efficacy. IBOP (24 h) did not affect the expression or phosphorylation of connexin 43 in whole HEC lysates. Immunohistologic examination of HEC suggested that IBOP may impair functional coupling by altering the cellular distribution of gap junctions, leading to increased connexin 43 internalization. Thus, this finding that TXA(2) mimetics can prevent HEC migration and tube formation, possibly by impairing intercellular communication, suggests that antagonizing TXA(2) signaling might enhance vascularization of ischemic tissue.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed1999

Enhancement of endothelial cell migration and in vitro tube formation by TAP20, a novel beta 5 integrin-modulating, PKC theta-dependent protein.

Migration, proliferation, and tube formation of endothelial cells are regulated by a protein kinase C isoenzyme PKCtheta. A full-length cDNA encoding a novel 20-kD protein, whose expression was PKCtheta-dependent, was identified in endothelial cells, cloned, characterized, and designated as theta-associated protein (TAP) 20. Overexpression of TAP20 decreased cell adhesion and enhanced migration on vitronectin and tube formation in three-dimensional culture. An antiintegrin alphavbeta5 antibody prevented these TAP20 effects. Overexpression of TAP20 also decreased focal adhesion formation in alphavbeta3-deficient cells. The interaction between TAP20 and beta5 integrin cytoplasmic domain was demonstrated by protein coprecipitation and immunoblotting. Thus, the discovery of TAP20, which interacts with integrin beta5 and modulates cell adhesion, migration, and tube formation, further defines a possible pathway to angiogenesis dependent on PKCtheta.

Amino Acid Sequence↗
PubMed1999

Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, double-blind, placebo-controlled trial.

BACKGROUND: Angiogenesis is a promising treatment strategy for patients who are not candidates for standard revascularization, because it promotes the growth of new blood vessels in ischemic myocardium. METHODS AND RESULTS: We conducted a randomized, double-blind, placebo-controlled study of basic fibroblast growth factor (bFGF; 10 or 100 microg versus placebo) delivered via sustained-release heparin-alginate microcapsules implanted in ischemic and viable but ungraftable myocardial territories in patients undergoing CABG. Twenty-four patients were randomized to 10 microg of bFGF (n=8), 100 microg of bFGF (n=8), or placebo (n=8), in addition to undergoing CABG. There were 2 operative deaths and 3 Q-wave myocardial infarctions. There were no treatment-related adverse events, and there was no rise in serum bFGF levels. Clinical follow-up was available for all patients (16.0+/-6.8 months). Three control patients had recurrent angina, 2 of whom required repeat revascularization. One patient in the 10-microg bFGF group had angina, whereas all patients in the 100-microg bFGF group remained angina-free. Stress nuclear perfusion imaging at baseline and 3 months after CABG showed a trend toward worsening of the defect size in the placebo group (20.7+/-3.7% to 23.8+/-5.7%, P=0.06), no significant change in the 10-microg bFGF group, and significant improvement in the 100-microg bFGF group (19.2+/-5.0% to 9.1+/-5.9%, P=0.01). Magnetic resonance assessment of the target ischemic zone in a subset of patients showed a trend toward a reduction in the target ischemic area in the 100-microg bFGF group (10.7+/-3.9% to 3. 7+/-6.3%, P=0.06). CONCLUSIONS: This study of bFGF in patients undergoing CABG demonstrates the safety and feasibility of this mode of therapy in patients with viable myocardium that cannot be adequately revascularized.

Alginates↗
PubMed1999

Downregulation of protein kinase cdelta activity enhances endothelial cell adaptation to hypoxia.

BACKGROUND: Although protein kinase C (PKC) has been implicated in ischemic cell death, the role of individual PKC isoenzymes in the response of endothelial cells (ECs) to hypoxia is unknown. METHODS AND RESULTS: To test the effect of hypoxia on the activity of individual PKC isoenzymes, human ECs were exposed to 95% N(2) with 5% CO(2) for 24 hours. This severe hypoxia reduced PKCdelta specific activity in both human umbilical vein ECs (HUVECs) and a HUVEC-derived EC line (ECVs) significantly (80.5+/-5.7% and 55.5+/-8. 6% of normoxia controls, respectively); the activities of PKCalpha and PKCepsilon were unchanged. The protein levels of PKCalpha, PKCdelta, and PKCepsilon were unchanged by hypoxia. To determine whether PKCdelta downregulation by hypoxia was linked to EC function, ECVs in which PKCdelta was stably overexpressed (PKCdelta-ECs) were exposed to hypoxia. A significant increase in cell death was observed in PKCdelta-ECs compared with controls (5.8+/-0.6% versus 2. 3+/-0.4% at 24 hours, 13.2+/-1.2% versus 4.1+/-0.4% at 48 hours, P<0. 05) during hypoxia. Neither the DNA laddering assay nor TUNEL staining revealed an increase in apoptosis of PKCdelta-ECs exposed to hypoxia, suggesting a hypoxia-induced increase in nonapoptotic cell death of PKCdelta-ECs. Inhibition of NO synthase with N(G)-monomethyl-L-arginine (L-NMMA) affected neither the decline in PKCdelta activity nor the EC death induced by hypoxia. CONCLUSIONS: PKCdelta activity is decreased by hypoxia by a mechanism that does not involve NO synthase; this downregulation appears to enhance EC survival during hypoxia by decreasing nonapoptotic cell death.

Adaptation, Physiological↗
PubMed1999

Vascular endothelial growth factor-induced endothelial cell migration and proliferation depend on a nitric oxide-mediated decrease in protein kinase Cdelta activity.

Vascular endothelial growth factor (VEGF) promotes angiogenesis and endothelial cell (EC) migration and proliferation by affecting intracellular mediators, only some of which are known, distal to its receptors. Protein kinase C (PKC) participates in the function of VEGF, but the role of individual PKC isoenzymes is unknown. In this study, we tested the importance of the activity of specific PKC isoenzymes in human EC migration and proliferation in response to VEGF. PKCdelta specific activity was depressed by the addition of VEGF (by 41+/-8% [P<0.05] at 24 hours) in human umbilical vein ECs (HUVECs) and in a HUVEC-derived EC line, ECV, without changing the total amount of either protein or mRNA encoding PKCdelta. Neither basic fibroblast growth factor (FGF-2) nor serum altered PKCdelta specific activity. The VEGF-induced decrease of PKCdelta activity, which began at 8 hours after stimulation, was strongly blocked by pretreatment with the nitric oxide (NO) synthase inhibitor N(G)-monomethyl-L-arginine in HUVECs; NO release peaked within 2 hours after stimulation. An exogenous NO donor, sodium nitroprusside, also decreased PKCdelta activity. The inhibition by N(G)-monomethyl-L-arginine of VEGF-induced HUVEC migration and proliferation, but not that induced by FGF-2 or serum, suggested that the decrease in PKCdelta via NO pathway is required for VEGF-induced EC migration and proliferation. Overexpression of PKCdelta in ECV cells specifically prevented EC response to VEGF but not to FGF-2 or serum. Thus, we conclude that suppression of PKCdelta activity via a NO synthase mechanism is required for VEGF-induced EC migration and proliferation, but not for that induced by FGF-2 or serum.

Cell Division↗
PubMed1999

Protein kinase Cdelta inhibition of S-phase transition in capillary endothelial cells involves the cyclin-dependent kinase inhibitor p27(Kip1).

Distinct protein kinase C (PKC) isoforms differentially regulate cellular proliferation in rat microvascular endothelial cells (EC). Overexpression of PKCalpha has little effect on proliferation, whereas PKCdelta slows endothelial cell proliferation and induces S-phase arrest. Analyses were performed on EC overexpressing PKCalpha (PKCalphaEC) or PKCdelta (PKCdeltaEC) to determine the role of specific cell cycle regulatory proteins in the PKCdelta-induced cell cycle arrest. Serum-induced stimulation of cyclins D1, E, and A-associated kinase activity was delayed by 12 h in the PKCdeltaEC line in association with S-phase arrest. However, the protein levels for cyclins D1, E, and A were similar. Nuclear accumulation of cyclin D1 protein in response to serum was also delayed in PKCdeltaEC. In the PKCdeltaEC line, serum induced p27(Kip1) but not p16(Ink4a) or p21(Cip1). Serum did not affect p27(Kip1) levels in the control vascular endothelial cell line. Immunoprecipitation-Western blotting analysis of p27(Kip1) showed serum stimulation of the vascular endothelial cell line resulted in increased amounts of cyclin D1 bound to p27(Kip1). In the PKCdeltaEC line, serum did not increase the amount of cyclin D1 bound to p27(Kip1). Transfection of full-length p27(Kip1) antisense into the PCKdeltaEC line reversed the S-phase arrest and resulted in normal cell cycle progression, suggesting a critical role for p27(Kip1) in the PKCdelta-mediated S-phase arrest.

Animals↗
PubMed1999

Angiogenesis activators and inhibitors differentially regulate caveolin-1 expression and caveolae formation in vascular endothelial cells. Angiogenesis inhibitors block vascular endothelial growth factor-induced down-regulation of caveolin-1.

Angiogenesis is the process by which new blood vessels are formed via proliferation of vascular endothelial cells. A variety of angiogenesis inhibitors that antagonize the effects of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have recently been identified. However, the mechanism by which these diverse angiogenesis inhibitors exert their common effects remains largely unknown. Caveolin-1 and -2 are known to be highly expressed in vascular endothelial cells both in vitro and in vivo. Here, we examine the potential role of caveolins in the angiogenic response. For this purpose, we used the well established human umbilical vein endothelial cell line, ECV 304. Treatment of ECV 304 cells with known angiogenic growth factors (VEGF, bFGF, or hepatocyte growth factor/scatter factor), resulted in a dramatic reduction in the expression of caveolin-1. This down-regulation event was selective for caveolin-1, as caveolin-2 levels remained constant under these conditions of growth factor stimulation. VEGF-induced down-regulation of caveolin-1 expression also resulted in the morphological loss of cell surface caveolae organelles as seen by transmission electron microscopy. A variety of well characterized angiogenesis inhibitors (including angiostatin, fumagillin, 2-methoxy estradiol, transforming growth factor-beta, and thalidomide) effectively blocked VEGF-induced down-regulation of caveolin-1 as seen by immunoblotting and immunofluorescence microscopy. However, treatment with angiogenesis inhibitors alone did not significantly affect the expression of caveolin-1. PD98059, a specific inhibitor of mitogen-activated protein kinase and a known angiogenesis inhibitor, also blocked the observed VEGF-induced down-regulation of caveolin-1. Furthermore, we show that caveolin-1 can function as a negative regulator of VEGF-R (KDR) signal transduction in vivo. Thus, down-regulation of caveolin-1 may be an important step along the pathway toward endothelial cell proliferation.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

Cyclooxygenase inhibitors increase Na-K-2Cl cotransporter abundance in thick ascending limb of Henle's loop.

Cyclooxygenase inhibitors, such as indomethacin and diclofenac, have well-described effects to enhance renal water reabsorption and urinary concentrating ability. Concentrating ability is regulated in part at the level of the thick ascending limb of Henle's loop, where active NaCl absorption drives the countercurrent multiplication mechanism. We used semiquantitative immunoblotting to test the effects of indomethacin and diclofenac, given over a 48-h period, on the expression levels of the ion transporters responsible for active NaCl transport in the thick ascending limb. Both agents strongly increased the expression level of the apical Na-K-2Cl cotransporter in both outer medulla and cortex. Neither agent significantly altered outer medullary expression levels of other thick ascending limb proteins, namely, the type 3 Na/H exchanger (NHE-3), Tamm-Horsfall protein, or alpha1- or beta1-subunits of the Na-K-ATPase. Administration of the EP3-selective PGE(2) analog, misoprostol, to indomethacin-treated rats reversed the stimulatory effect of indomethacin on Na-K-2Cl cotransporter expression. We conclude that cyclooxygenase inhibitors enhance urinary concentrating ability in part through effects to increase Na-K-2Cl cotransporter expression in the thick ascending limb of Henle's loop. This action is most likely due to elimination of an EP3-receptor-mediated tonic inhibitory effect of PGE(2) on cAMP production.

Animals↗
PubMed1998

Myb-dependent regulation of thrombospondin 2 expression. Role of mRNA stability.

The nuclear transcription factor c-Myb, which is highly expressed in hematopoietic cells, has been shown to be functional in NIH 3T3 cells: cells that do not possess detectable levels of c-Myb. To identify endogenous target genes of c-Myb in fibroblasts, RNA isolated from NIH 3T3 cells stably transfected with a full-length or a dominant negative c-myb construct (GREMyb and GREMEn, respectively) was subjected to differential display analysis. 5'-Rapid amplification of cDNA ends of a selected band, sequencing, and a nucleotide homology search led to the identification of thrombospondin 2 (TSP 2) as the gene product repressed in GREMyb and induced in GREMEn cells. The pattern of TSP 2 expression during the cell cycle was consistent with c-myb-dependent regulation. The possibility that the identified transcript was TSP 1, a homologous product known to be repressed by v-Src, c-Jun, and v-Myc, was ruled out by using a TSP 2-specific DNA probe and by showing a distinct pattern of regulation of TSP 1 and TSP 2 expression. Nuclear run-on and TSP 2 promoter-reporter (chloramphenicol acetyltransferase) assays showed similar transcriptional levels in GREMyb and NIH 3T3 cells. However, mRNA stability studies showed a much shorter TSP 2 mRNA half-life in GREMyb compared with wild type NIH 3T3 cells, suggesting that c-myb affects TSP 2 expression via a post-transcriptional mechanism. The implications of a protooncogene-mediated suppression of TSP expression are discussed.

3T3 Cells↗
PubMed1998

Cellular distribution of N-acetyltransferase activity in the rat small intestine.

The cellular distribution of AcCoA:arylamine N-acetyltransferase (NAT; EC 2.3.1.5) activities was examined in the rat small intestine to determine if heterogeneous cellular distribution contributes to preferential tumor development in the colonic region after exposure to heterocyclic amines (HAs). A chelation/elution method was used to preferentially isolate villus-tip, mid-villus, and crypt enterocytes. Monomorphic (NAT1) and polymorphic (NAT2) activities were determined using N-acetylprocainamide and N-acetamidobenzoic acid formation, respectively. Sucrase-isomaltase (SI) activity was used to confirm that a villus, mid-villus, and crypt cell gradient had been obtained. Utilizing this marker of villus enrichment, a 4- to 10-fold gradient was achieved. NAT1 and NAT2 activities followed this gradient, with the highest NAT activity occurring in the fraction with the highest SI activity. The ratio of NAT2:NAT1 remained essentially constant along the gradient, indicating a similar pattern of expression for both enzymes. This pattern of cellular distribution for the NATs is similar to that reported for cytochrome P450s. This apparent preferential expression of NAT in the villus cells may result in delivery of bioactivated HAs to the lower regions of the intestines as the villus-tip cells are extruded into the intestinal lumen and enter the fecal stream.

Animals↗
PubMed1998

Immunochemical detection and identification of protein adducts of diclofenac in the small intestine of rats: possible role in allergic reactions.

Idiosyncratic adverse drug reactions are unpredictable, target multiple organ systems, and often become life-threatening events. Although the causes of idiosyncratic adverse drug reactions are not known in most cases, evidence suggests that they may be mediated through immunological mechanisms. It is generally thought that for a drug to lead to an immune response, it must first become covalently bound to a carrier protein. Since most drugs are unreactive, it is usually a reactive metabolite that is expected to form covalent adducts. However, it is not clear why more people do not develop immune reactions against drug-protein adducts. One possible explanation is that orally administered drugs may lead to oral tolerance in most individuals through mechanisms similar to that found with orally administered antigens. However, very little is known regarding the interaction of drugs with gut-associated lymphoid tissue of the small intestine, where oral tolerance can develop. As an initial step to test this hypothesis, we have investigated whether diclofenac, a commonly used nonsteroidal antiinflammatory drug, can lead to protein adducts in rat small intestine. Diclofenac was administered to rats by gastric gavage. Immunoblot analysis of small intestine homogenates and isolated enterocyte subcellular fractions with drug-specific antiserum revealed 142-, 130-, 110-, and 55-kDa protein adducts of diclofenac. The 142- and 130-kDa adducts of diclofenac were identified as aminopeptidase N (CD13) and sucrase-isomaltase, respectively, by amino acid sequence analyses and by their reactions with protein-specific antibodies. The adducts were localized by immunohistochemistry and found primarily in the mid-villus and villus-tip enterocytes and also in the dome overlying Peyer's patches. Similar adducts were detected immunochemically in villus-tip enterocytes of animals treated with halothane or acetaminophen. These results show that intestinal protein adducts of drugs can be formed in gut-associated lymphoid tissue where they may lead to the down-regulation of drug-induced allergic reactions in many individuals.

Acetaminophen↗
PubMed1997

Requirement for protein kinase C theta for cell cycle progression and formation of actin stress fibers and filopodia in vascular endothelial cells.

Activation of the protein kinase C (PKC) family with phorbol esters induces endothelial proliferation and angiogenesis, but which of the events that constitute angiogenesis are affected by individual members of the PKC family is unknown. In rat capillary endothelial (RCE) cells, serum stimulation increased expression of a single PKC isoenzyme, PKCtheta, and its translocation to the periphery. Conditional overexpression of a dominant-negative mutant of PKCtheta markedly inhibited RCE proliferation, as well as closure of a "wound" by RCE migration and formation of capillary rings and tubules in vitro. PKCtheta inhibition delayed the endothelial cell cycle at the G2/M phase and prevented formation of actin stress fibers and filopodia but not lamellipodia. The defect in cell morphology and wound closure in PKCtheta-kn cells was reversed by overexpressing kinase-active PKCtheta, indicating that these RCE functions depend upon PKCtheta substrates. Thus, PKCtheta is required for multiple processes essential for angiogenesis and wound repair, including endothelial mitosis, maintenance of a normal actin cytoskeleton, and formation of an enclosed tube.

Actins↗