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PubMed2002

Distribution patterns of PCNA and ANP in perinatal stages of the developing rat heart.

Distribution patterns of proliferating cell nuclear antigen (PCNA) and atrial natriuretic peptide (ANP) were determined immunohistochemically and morphometrically in atrium and ventriculum of the developing rat heart in different stages of the perinatal period. During the prenatal period, PCNA and ANP were localized in opposite patterns, particularly in trabecular myocytes. A distinct reduction in the percentage of PCNA-positive nuclei was detected starting at day 19 of the prenatal period, and these cells were rarely observed on postnatal days 30 and 60. In cardiomyocytes, a distinct increase in ANP positivity was found, whereas PCNA positivity was very low. It is concluded that PCNA expression gradually decreased from prenatal day 19 onwards, whereas ANP expression increased in atria throughout the prenatal and postnatal periods, except for a decrease in ANP expression in ventricles from prenatal day 21 onwards. The opposite expression patterns of PCNA and ANP in trabecular myocytes of ventricles indicate that ANP may have antimitogenic/antiproliferative effects in trabecular myocytes.

Animals↗
PubMed1998

Lack of beneficial effects of growth hormone treatment in conscious dogs during development of heart failure.

The effects of chronic treatment with growth hormone (porcine GH, 0.56 mg.kg-1.day-1 s.c.) were examined in dogs with heart failure induced by rapid ventricular pacing (240 beats/min) for 4 wk. Fourteen conscious dogs were studied 2-3 wk after surgical instrumentation with catheters in the descending aorta and left atrium, a pressure gauge in the left ventricle (LV), a flow probe around the ascending aorta, pacing leads on the ventricular free wall and left atrium, and ultrasonic crystals on the opposing anterior and posterior endomyocardium of the LV. GH treatment for 4 wk significantly increased both body weight and plasma insulin-like growth factor 1 (IGF-1) compared with vehicle-treated dogs (P < 0.01, +2.0 +/- 0.5 vs. +0.3 +/- 1.1 kg; 1,043 +/- 218 vs. 241 +/- 64 ng/ml, respectively). However, the changes in resting LV systolic (i.e., both isovolumic and ejection phases) and diastolic function (i.e., isovolumic relaxation time constant tau) and the systemic vascular resistance were similar for the GH- and vehicle-treated groups during the development of heart failure. LV contractile reserve, assessed with step infusion of isoproterenol or dobutamine challenge, was markedly attenuated after heart failure, but there were no differences between the GH- and vehicle-treated groups. During the progression of heart failure, the increases in plasma atrial natriuretic peptide correlated (P < 0.01) directly with left atrial pressure and inversely with LV circumferential fiber shortening. However, GH treatment did not substantially modify these relationships. In addition, renal function and myocardial ultrastructure at the advanced stage of heart failure also showed similar changes for the GH- and vehicle-treated groups. We conclude that in conscious dogs during the development of congestive heart failure produced by rapid ventricular pacing, GH at a dose that increases body weight and plasma IGF-1 levels does not affect LV performance or systemic vascular dynamics.

Adrenergic beta-Agonists↗
PubMed1994

Cloning and developmental expression of the chick type II and type III TGF beta receptors.

To address the role of peptide growth factors in chick organogenesis, we have focused on TGF beta 2 and have cloned the chick Type II and Type III TGF beta receptors. The chick Type II receptor is a serine/threonine kinase with a ligand binding profile identical to the human receptor and a divergent N-terminus when compared to the mammalian receptors. The chick Type III receptor is a beta-glycan that demonstrates a binding profile identical to the rat receptor and contains a single transmembrane spanning domain and short cytoplasmic tail that are highly conserved when compared to the mammalian receptors. Both the Type II and Type III TGF beta receptors are coexpressed during chick embryogenesis in the developing heart, lung, and eye, and are developmentally upregulated in parallel in the heart and lung. Levels of both receptor proteins and mRNAs also increase in cardiocytes cultured from different developmental stages, in agreement with the increase in Type II and Type III receptor mRNA levels observed in the developing heart. Although exhibiting different temporal or spatial profiles from the receptors, TGF beta 2 is also expressed in the developing heart, lung, and eye. These findings are consistent with recent data indicating that co-expression of both the Type II and Type III TGF beta receptors is required for high affinity binding of TGF beta 2 by the Type II receptor and suggest that TGF beta 2 and the Type II and Type III TGF beta receptors participate in heart, lung, and eye development.

Amino Acid Sequence↗
PubMed1996

Contribution of sarcolemmal calcium current to total cellular calcium in postnatally developing rat heart.

OBJECTIVE: The aim was to determine the contribution of sarcolemmal Ca influx through L-type Ca current to total cellular Ca in newborn and postnatally developing rat heart. METHODS: Whole cell voltage clamp was used to study L-type Ca current in freshly isolated ventricular cells of 1, 6, 10, 15, 30-day-old and adult (120-150 days) rats. Amplitude, current density, inactivation rate and time integral of Ca current were determined at the experimental temperature of 36 degrees C. Width, length, surface area, volume and surface-to-volume ratio of the isolated cells were also determined. Using the time integral of Ca current and volume of the myocytes the increment in total cellular Ca was calculated for the six developmental stages. RESULTS: The amplitude of Ca current increased strongly during the postnatal maturation from 277 +/- 25 pA at day 1 to 1961 +/- 98 pA in the adult rat (P < 0.001). This increase was due to an almost proportional increase in cell size; accordingly the density of Ca current remained fairly constant, being 16.9 +/- 1.8, 17.0 +/- 1.8, 22.8 +/- 1.4, 21.2 +/- 1.5, 16.2 +/- 2.0 and 15.9 +/- 0.7 pA/pF for 1, 6, 10, 15, 30-day-old and adult rats, respectively. Charge transfer by Cd-sensitive Ca current during 200 ms voltage pulse from -45 mV to 0 mV increased from 7.18 +/- 1.00 pC at day one to 24.80 +/- 1.80 pC in the adult rat heart (P < 0.001). When normalized to the capacitive surface area of the myocytes the charge transfer by L-type Ca current was more than double in newborns (0.429 +/- 0.074 pC/pF) as compared to the adults (0.188 +/- 0.016 pC/pF) (P < 0.01). The difference is explained by slower inactivation rate of Ca current in newborn than adult rats. Time constant of the fast component was 5.92 +/- 0.62 ms and 4.5 +/- 0.4 ms (P < 0.05) for 1-day-old and adult rat, respectively. Time constant of the slow component decreased from 27.7 +/- 2.0 to 21.7 +/- 3.0, although the difference was not statistically significant (P = 0.26). The increment in total cellular Ca due to Ca influx through Ca channels was 54 +/- 9 mumol l-1 in 1-day-old rat and decreased steadily during postnatal maturation to 8 +/- 1 mumol l-1 in the adult rat (P < 0.001). The change is partly due to faster inactivation of Ca current in adults but mainly as a consequence of decreasing surface-to-volume ratio of growing myocytes. Sarcolemmal surface area increases almost 9 times from 1.001 x 10(3) microns2 at day 1 to 8.675 x 10(3) microns2 for the adult rat, whereas increase in cell volume is about 28-fold from 0.991 x 10(3) to 27.74 x 10(3) microns3: accordingly surface-to-volume ratio decreases from 1.05 +/- 0.02 at day 1 to 0.36 +/- 0.01 in the adult rat (P < 0.01). CONCLUSIONS: Contribution of sarcolemmal Ca influx through L-type Ca channels is over 6 times higher in newborn than mature rats. Therefore, the strong dependence of neonatal rat heart on extracellular Ca for contractile activation is, at least partially, explained by greater contribution of L-type Ca current to intracellular Ca.

Animals↗
PubMed1999

Misregulation of connexin43 gap junction channels and congenital heart defects.

Although there is general agreement that gap junction channels formed by the connexin43 (Cx43; alpha 1) protein most likely have important roles during heart development, evidence to support this view has been equivocal. Lacking this information, it is difficult to understand the basis of heart malformations found in the Cx43 knockout mice and in children with a severe form of visceroatrial heterotaxia that coincides with missense mutations of the Cx43 gene. To address this issue we used a combination of western blots to follow the emergence of Cx43 in heart, and in vitro and in vivo phosphorylation to assess the effect of mutation on Cx43 phosphorylation. We evaluated the activity ratios of cAMP-dependent protein kinase and protein kinase C in hearts of 8.5-day-old mouse embryos through to birth. The results demonstrate that Cx43 is present in the native phosphorylated species in day 8.5 hearts and thereafter. Further, the activities of cAMP-dependent protein kinase and protein kinase C are mirror images of each other during the 8.5-10.5 days of early heart development. From these results we conclude that Cx43 gap junction channels are present and capable of being regulated by day 8.5 of embryonic heart development.

Amino Acid Sequence↗
PubMed2003

PITX2 isoform-specific regulation of atrial natriuretic factor expression: synergism and repression with Nkx2.5.

PITX2 and Nkx2.5 are two of the earliest known transcriptional markers of vertebrate heart development. Pitx2-/- mice present with severe cardiac malformations and embryonic lethality, demonstrating a role for PITX2 in heart development. However, little is known about the downstream targets of PITX2 in cardiogenesis. We report here that the atrial natriuretic factor (ANF) promoter is a target of PITX2. PITX2A, PITX2B, and PITX2C isoforms differentially activate the ANF promoter. However, only PITX2C can synergistically activate the ANF promoter in the presence of Nkx2.5. We further demonstrate that the procollagen lysyl hydroxylase (PLOD1) promoter is regulated by Nkx2.5. Mechanistically, PITX2C and Nkx2.5 synergistically regulate ANF and PLOD1 expression through binding to their respective DNA elements. Surprisingly, PITX2A activation of the ANF and PLOD1 promoters is repressed by co-transfection of Nkx2.5 in the C3H10T1/2 embryonic fibroblast cell line. Pitx2a and Pitx2c are endogenously expressed in C3H10T1/2 cells, and these cells express factors that differentially regulate PITX2 isoform activities. We provide a new mechanism for the regulation of heart development by PITX2 isoforms through the regulation of ANF and PLOD1 gene expression and Nkx2.5 transcriptional activity.

Animals↗
PubMed1997

Expression and regulation of 80K/MARCKS, a major substrate of protein kinase C, in the developing rat heart.

OBJECTIVE: Protein kinase C (PKC) plays a pivotal role in modulating the growth and differentiation of many cell types including the cardiac myocyte. However, little is known about molecules that act immediately downstream of PKC in the heart. In this study we have investigated the expression of 80K/MARCKS, a major PKC substrate, in whole ventricles and in cardiac myocytes from developing rat hearts. METHODS: Poly A/ RNA was prepared from neonatal (2-day) and adult (42-day) cardiac myocytes and whole ventricular tissue and mRNA expression determined by reverse transcription-polymerase chain reaction (RT-PCR) using primers designed to identify a 420 bp fragment in the 80K/MARCKS gene. Protein extracts were prepared from either 2-day and 42 day cardiac myocytes or from whole ventricular tissue at 2, 5-11, 14, 17, 21, 28 and 42 days of age. Protein expression was determined by immunoblotting with an 80/MARCKS antipeptide antibody and PKC activity was determined by measuring the amount of gamma 32 P-ATP transferred to a specific peptide substrate. RESULTS: RT-PCR analysis of 80K/MARCKS mRNA in neonatal (2-day) and adult (42-day) cardiac myocytes showed the expression of this gene in both cell types. Immunoblotting revealed maximum 80K/MARCKS protein expression in whole ventricular tissue at 5 days (a 75% increase above values at 2 days), followed by a transient decrease in expression during the 6-8 day period (61% of the protein expressed at 2 days for 8-day tissue) with levels returning to 5 day levels by 11 days of age. 80K/MARCKS protein was present in cardiac myocytes at 2 days of age whereas it was not detectable in adult cells. In addition, PKC activity levels increased to 160% of levels present at 2 days in 8-day old ventricles with PKC activity levels returning to 5-day levels by 9 days of age. This was then; followed by a steady decline in both 80K/MARCKS protein expression and PKC activity through to adulthood. CONCLUSIONS: Expression of the PKC substrate, 80K/MARCKS, in cardiac myocytes changes significantly during development and the transient loss of immunoreactive protein during the 6-8 day development period may reflect 80K/MARCKS phosphorylation and subsequent down-regulation as a result of the concomitant up-regulation of PKC activity at this time.

Animals↗
PubMed1976

Effects of neonatal or maternal methadone administration on ornithine decarboxylase activity in brain and heart of developing rats.

Methadone was administered daily to pregnant or nursing rats, or directly to neonates, and the effects on brain and heart weights and ornithine decarboxylase (ODC) activities were determined during postnatal development. Exposure to methadone in the postnatal period either directly or via the mother resulted in delays in maturational decreases in brain ODC accompanied by deficits in brain weight. Prenatal exposure alone had less effect on brain weight or ODC but appeared to enhance the effect of subsequent methadone exposure during the postnatal period. In the heart, direct methadone exposure or prenatal plus postnatal maternal administration led to a pattern of altered ODC activity consistent with delayed development, accompanied by heart weight deficits. The disturbance of heart ODC development after purely prenatal or purely postnatal maternal exposures differed from that obtained after direct administration to the neonate. These data show that exposure to methadone during fetal and/or neonatal life produces alterations in polyamine metabolism which may result in abnormal organ development. The type of change is dependent upon the period and route of exposure and may reflect both direct effects on the pup and indirect effect from drug-induced alterations in maternal metabolism or behavior.

Aging↗
PubMed2000

Expression and regulation of pyruvate dehydrogenase kinase isoforms in the developing rat heart and in adulthood: role of thyroid hormone status and lipid supply.

Activation of the pyruvate dehydrogenase (PDH) complex (PDHC) promotes glucose disposal, whereas inactivation conserves glucose. The PDH kinases (PDHKs) regulate glucose oxidation through inhibitory phosphorylation of PDHC. The adult rat heart contains three PDHK isoforms PDHK1, PDHK2 and PDHK4. Using Western-blot analysis, with specific antibodies raised against individual recombinant PDHK1, PDHK2 and PDHK4, the present study investigated PDHK isoform expression in the developing rat heart and adulthood. We identified clear differences in the patterns of protein expression of each of these PDHK isoforms during the first 3 weeks of post-natal development, with most marked up-regulation of isoforms PDHK1 and PDHK4. Distinctions between the three cardiac PDHK isoforms were also demonstrated with respect to post-neonatal maturational up-regulation; with greatest up-regulation of PDHK1 and least up-regulation of PDHK4 from the post-neonatal period until maturity. The study also examined the role of thyroid hormone status and lipid supply on PDHK isoform expression. We observed marked selective increases in the amount of PDHK4 protein present relative to total cardiac protein in both hyperthyroidism and high-fat feeding. Overall, our data identify PDHK isoform PDHK1 as being of more potential regulatory importance for glucose oxidation in the adult compared with the neonatal heart, and cardiac PDHK4 as a PDHK isoform whose expression is specifically responsive to changes in lipid supply, suggesting that its up-regulation during early post-natal life may be the perinatal switch to use fatty acids as the energy source. We also identify regulation of pyruvate sensitivity of cardiac PDHK as a physiological variable, a change in which requires factors in addition to a change in lipid supply.

Aging↗
PubMed1983

Changes in the endothelial morphology of the developing semilunar heart valves. A TEM and SEM study in the chick.

In view of recent evidence showing that shape and orientation of endothelial cells is determined by blood flow, the endothelium of the semilunar valves was studied in the developing chick heart using transmission and scanning electron microscopy. The results reveal significant developmental modifications of endothelial morphology and structure. These modifications can be linked to modifications of local blood flow and can also explain several aspects of valvular morphogenesis. The results substantially support the hypothesis of an involvement of hemodynamics in the development of the semilunar valves.

Animals↗
PubMed1996

Nonuniform elasticity of titin in cardiac myocytes: a study using immunoelectron microscopy and cellular mechanics.

Titin (also known as connectin) is a muscle-specific giant protein found inside the sarcomere, spanning from the Z-line to the M-line. The I-band segment of titin is considered to function as a molecular spring that develops tension when sarcomeres are stretched (passive tension). Recent studies on skeletal muscle indicate that it is not the entire I-band segment of titin that behaves as a spring; some sections are inelastic and do not take part in the development of passive tension. To better understand the mechanism of passive tension development in the heart, where passive tension plays an essential role in the pumping function, we investigated titin's elastic segment in cardiac myocytes using structural and mechanical techniques. Single cardiac myocytes were stretched by various amounts and then immunolabeled and processed for electron microscopy in the stretched state. Monoclonal antibodies that recognize different titin epitopes were used, and the locations of the titin epitopes in the sarcomere were studied as a function of sarcomere length. We found that only a small region of the I-band segment of titin is elastic; its contour length is estimated at approximately 75 nm, which is only approximately 40% of the total I-band segment of titin. Passive tension measurements indicated that the fundamental determinant of how much passive tension the heart develops is the strain of titin's elastic segment. Furthermore, we found evidence that in sarcomeres that are slack (length, approximately 1.85 microns) the elastic titin segment is highly folded on top of itself. Based on the data, we propose a two-stage mechanism of passive tension development in the heart, in which, between sarcomere lengths of approximately 1.85 microns and approximately 2.0 microns, titin's elastic segment straightens and, at lengths longer than approximately 2.0 microns, the molecular domains that make up titin's elastic segment unravel. Sarcomere shortening to lengths below slack (approximately 1.85 microns) also results in straightening of the elastic titin segment, giving rise to a force that opposes shortening and that tends to bring sarcomeres back to their slack length.

Animals↗
PubMed2005

ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society.

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Adult↗
PubMed1997

Overview of the molecular mechanisms of cardiac development.

Over the past 4 years remarkable progress has been made in the field of heart development. Several genes that regulate heart development in various model organisms have been cloned, and their functions have been analyzed in vitro and in vivo using molecular biological and genetic engineering techniques. We expect that understanding the molecular mechanisms of cardiac development will lead to better understanding of the pathogenesis of congenital heart disease and hopefully to new therapeutic approaches not only to congenital heart disease but also acquired heart disease such as heart failure.

Animals↗
PubMed2004

A cardiac-specific health-related quality of life module for young adults with congenital heart disease: development and validation.

This study represents the development and validation of a cardiac-specific module of the generic health-related quality of life (HRQoL) instrument, the TAAQOL (TNO/AZL Adult Quality Of Life), for young adults with congenital heart disease (CHD). Items were selected based on literature, an explorative previous study in CHD patients, interviews with patients, and the advice of experts. The newly developed Congenital Heart Disease-TNO/AZL Adult Quality of Life (CHD-TAAQOL) was tested in 156 patients with mild or complex CHD and consisted of three hypothesised subject scales: 'Symptoms' (9 items), 'Impact Cardiac Surveillance' (7 items), and 'Worries' (10 items). Cronbach's alpha for the three scales were 0.77, 0.78, and 0.82, respectively. Scale structure was confirmed by Principal Component Analysis, corrected item-scale and interscale correlations. Overall, 55% of reported health status problems were associated with negative emotions, which is an argument for assessing HRQoL as a concept distinct from health status. Convergent validity with validated generic instruments (TAAQOL and Short Form-36, SF-36) showed satisfactory coefficients. Discriminant validity was proven by significantly higher scores for mild CHD patients compared with those with complex CHD. In conclusion, the CHD-TAAQOL module together with the generic TAAQOL can be used to assess group differences for cardiac-specific HRQoL in young adults with CHD. Testing psychometric properties of the CHD-TAAQOL shows satisfactory results. However, to detect changes in HRQoL over time, further research is needed.

Adolescent↗
PubMed1998

Persistent and heterogenous expression of the cyclin-dependent kinase inhibitor, p27KIP1, in rat hearts during development.

We have previously shown that there were differential and dramatic decreases of cyclin and cyclin-dependent kinase (CDK) activities in cardiomyocytes during the neonatal period. The activity of CDKs control cell cycle progression, and this activity is regulated positively and negatively by association of CDKs with cyclins and cyclin-dependent kinase inhibitors (CKIs), respectively. While the INK family (p15(INK4B)/p16(INK4A)/p18(INK4C)/p19(INK4D)) of CKIs is not detectable in hearts, the KIP/CIP family (p21(CIP1), p27(KIP1) and p57(KIP2)) of CKIs is detectable in most organs including the heart. Differential and dramatic changes of the KIP/CIP family (p21(CIP1), p27(KIP1) and p57(KIP2)) of CKIs were detected in rat hearts during development. The mRNA and protein levels of p21(CIP1) and p57(KIP2) were readily detectable in hearts at gestational and early postnatal periods and decreased thereafter. The mRNA levels of p27(KIP1) in ventricles were high during the gestational period, and did not change until day 30 postnatal, then were decreased slightly in 90-day-old rats. The protein levels of p27(KIP1) increased significantly in the early postnatal period, then were expressed persistently, although levels decreased slightly in the adult period. However, protein levels of p27(KIP1) in atria did not change during development. Variable immuno-staining patterns of p27(KIP1) were observed at different periods of development and in various locations in myocardium. During the gestational period, approximately 35-50% of myocardial cells in the cardiac wall were p27(KIP1) immuno-positive and were distributed diffusely. These p27(KIP1) immunopositive cells increased predominantly in endocardial and mid-portion areas of ventricular myocardium at the early postnatal period. This heterogenous pattern of p27(KIP1) protein expression persisted to adult hearts though the percentage of p27(KIP1) immuno-positive cells decreased slightly. High magnification revealed that more than 50% of adult cardiomyocytes were p27(KIP1) immuno-positive and that p27(KIP1) was located solely in nuclei. These results indicate that p27(KIP1) may be an important inhibitor of CDK activities in cardiomyocytes during early postnatal development and may block the re-entrance of adult cardiomyocytes into the cell cycle after injury.

Animals↗
PubMed2003

Development of heart muscle-cell diversity: a help or a hindrance for phenotyping embryonic stem cell-derived cardiomyocytes.

Despite the advances in cardiovascular treatment, cardiac disease remains a major cause of morbidity in all industrialized countries. The extraordinary potential of (embryonic) stem cells for therapeutic purposes has revolutionized ideas about cardiac repair of diseased cardiac muscle to exciting stages. This, in turn, has challenged research on cardiac differentiation of stem cells. For instance, cultures of mouse embryonic stem cells quite easily differentiate into the cardiogenic lineage, as assessed by their potential to beat spontaneously. However, repair of impaired cardiac muscle by spontaneously beating cardiac muscle cells might impose severe risks upon a human patient. Therefore, it is of crucial importance to understand the mechanisms that underlie the development of the distinct cardiac muscle cell types of the adult mammalian heart. In this review we tried to relate cardiac morphogenesis to the development of unique molecular phenotypes of cardiomyocytes. This relationship will provide a framework to assess the significance of the molecular phenotypes that are observed in embryonic stem cell-derived cardiomyocytes (ESDCs). Although for the phenotyping of ESDCs a comparison should be made with the phenotypes of the developing heart, so far none of the currently available markers allow unequivocal assignment of subtypes.

Animals↗
PubMed2006

Loss of HB-EGF in smooth muscle or endothelial cell lineages causes heart malformation.

Epidermal growth factor (EGF) and ErbB family molecules play a role in heart development and function. To investigate the role of EGF family member, heparin-binding EGF-like growth factor (HB-EGF) in heart development, smooth muscle and endothelial cell lineage-specific HB-EGF knockout mice were generated using the Cre/loxP system in combination with the SM22alpha or TIE2 promoter. HB-EGF knockout mice displayed enlarged heart valves, and over half of these mice died during the first postnatal week, while survivors showed cardiac hypertrophy. These results suggest that expression of HB-EGF in smooth muscle and/or endothelial cell lineages is essential for proper heart development and function in mice.

Animals↗
PubMed1999

Slug is a mediator of epithelial-mesenchymal cell transformation in the developing chicken heart.

An epithelial-mesenchymal cell transformation occurs during the development of the endocardial cushions in the atrioventricular (AV) canal of the heart. We hypothesized that the transcription factor Slug is required for this epithelial-mesenchymal cell transformation since Slug is required for similar transformations during gastrulation and neural crest differentiation in chicken embryos. We found by RT-PCR and immunostaining that the temporal and spatial localization of Slug in the embryonic chicken heart is consistent with a role for Slug in endocardial cushion formation. Moreover, we found that Slug expression by AV canal endothelial cells is induced by a signal provided by AV canal myocardium. Slug appears to be required for epithelial-mesenchymal cell transformation in the chicken heart since treatment of AV canal explants with antisense Slug oligodeoxynucleotides inhibited mesenchymal cell formation in vitro. Antisense Slug oligodeoxynucleotides prevented endothelial cell-cell separation, suggesting that Slug acts early in the transformation pathway.

Animals↗