Biomedical subjects

Pierre Meneton

Publications and source records attributed to Pierre Meneton.

At least 19 recordsLinked to original sources

PubMed2006

A second expressed kininogen gene in mice.

We isolated PCR, RNA ligase-mediated rapid amplification of cDNA ends (RLM-RACE-PCR)-, and RT-PCR-generated clones from mouse kininogen family transcripts. DNA sequencing indicated that the clones were from two distinct genes. One set (K1) is from the previously reported mouse kininogen gene. The second set (K2) has an open reading frame, is 93% identical to K1 in the overlapping nucleotide sequence, and, unlike T-kininogens in the rat, encodes a bradykinin motif identical to K1. We discovered that K2 exists with two different 5' ends. We used RT-PCR to determine the distribution and relative abundance of K1 and K2 mRNA in mouse tissues. K2 is transcribed and K1 and K2 are generally both expressed in the same tissues; however, they differ in their regulation of the alternative splicing event that yields either low-molecular-weight kininogen (LMWK) or high-molecular-weight kininogen (HMWK). For example, in the liver K1 is expressed as both HMWK and LMWK, whereas K2 is only expressed as LMWK. Conversely, in the kidney K2 is strongly expressed as both HMWK and LMWK, whereas K1 is not expressed as HMWK and expressed only very weakly as LMWK.

Animals↗

PubMed2006

Pendrin regulation in mouse kidney primarily is chloride-dependent.

Recent studies indicate that pendrin, an apical Cl-/HCO3- exchanger, mediates chloride reabsorption in the connecting tubule and the cortical collecting duct and therefore is involved in extracellular fluid volume regulation. The purpose of this study was to test whether pendrin is regulated in vivo primarily by factors that are associated with changes in renal chloride transport, by aldosterone, or by the combination of both determinants. For achievement of this goal, pendrin protein abundance was studied by semiquantitative immunoblotting in different mouse models with altered aldosterone secretion or tubular chloride transport, including NaCl loading, hydrochlorothiazide administration, NaCl co-transporter knockout mice, and mice with Liddle's mutation. The parallel regulation of the aldosterone-regulated epithelial sodium channel (ENaC) was examined as a control for biologic effects of aldosterone. Major changes in pendrin protein expression were found in experimental models that are associated with altered renal chloride transport, whereas no significant changes were detected in pendrin protein abundance in models with altered aldosterone secretion. Moreover, in response to hydrochlorothiazide administration, pendrin was downregulated despite a marked secondary hyperaldosteronism. In contrast, alpha-ENaC was markedly upregulated, and the molecular weight of a large fraction of gamma-ENaC subunits was shifted from 85 to 70 kD, consistent with previous results from rat models with elevated plasma aldosterone levels. These results suggest that factors that are associated with changes in distal chloride delivery govern pendrin expression in the connecting tubule and cortical collecting duct.

Aldosterone↗

PubMed2006

Mice chronically fed a westernized experimental diet as a model of obesity, metabolic syndrome and osteoporosis.

BACKGROUND: Most studies in animals use diets with several features (for example low-fat, rich in micronutriments), likely to be strongly protective against chronic diseases. AIM OF THE STUDY: The present study, performed in wild type outbred mice, was designed to evaluate the validity of a model of 'westernized' (W) diet reproducing, as closely as possible, the overall composition of an average human regime in western countries RESULTS: In contrast to the standard (S) diet, the W diet triggered a marked increase in adiposity with some characteristics of metabolic syndrome (hypercholesterolemia, hyperinsulinemia...). There was an heterogeneity in the propensity to become obese upon exposure to the W diet in female mice. Overweight mice also presented some disturbances of renal function, such as hyperalbuminuria and hypocitraturia. Mice adapted to the W diet showed a reduction of bone mineral density, especially the non-obese ones. CONCLUSION: These data suggest that a model of westernized diet could be appropriate for exploring the effects of mutations, drugs, or specific nutritional factors in animals and could be more relevant for human situations.

Animals↗

PubMed2006

Dietary sodium intake regulates the ubiquitin-protein ligase nedd4-2 in the renal collecting system.

The activity of the epithelial sodium (Na(+)) channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN) needs to be tightly regulated to match urinary Na(+) excretion with dietary Na(+) intake. The ubiquitin-protein ligase Nedd4-2, which in vitro interacts with ENaC subunits and reduces ENaC cell surface abundance and activity by ubiquitylation of the channel, may participate in the control of ENaC. This study confirms in vivo by reverse-transcriptase-PCR that Nedd4-2 is expressed throughout the nephron and is detectable by immunoblotting in kidney extracts. By immunohistochemistry, Nedd4-2 was found to be strongly expressed in the ASDN, with low staining intensity in the late distal convoluted tubule and early connecting tubule (where apical ENaC is high) and gradually increasing detection levels toward the collecting duct (CD; where apical ENaC is low). Compared with high-Na(+) diet (5% Na(+)), 2 wk of low-Na(+) diet (0.01% Na(+)) drastically reduces Nedd4-2 immunostaining and increases apical ENaC abundance in ASDN. Reduced Nedd4-2 immunostaining is not dependent on increased apical Na(+) entry in the CD, because it is similarly observed in mice with intact and with suppressed apical ENaC activity in the CD. Consistent with a role of mineralocorticoid hormones in the long-term regulation of Nedd4-2, 5-d treatment of cultured CD (mpkCCD(cl4)) cells with 1 microM aldosterone leads to reduction of Nedd4-2 protein expression. It is concluded that Nedd4-2 abundance is regulated by Na(+) diet, by a mechanism that likely involves aldosterone. This regulation may contribute to adaptation of apical ENaC activity to altered Na(+) intake.

Animals↗

PubMed2005

Tissue kallikrein-deficient mice display a defect in renal tubular calcium absorption.

Renal tubular calcium (RTCa) transport is one of the main factors that determine serum Ca concentration and urinary Ca excretion. The distal convoluted and connecting tubules reabsorb a significant fraction (10%) of filtered Ca. These tubule segments also synthesize in large abundance tissue kallikrein (TK), a major kinin-forming enzyme. Tested was the hypothesis that TK and kinins are involved in controlling RTCa transport by studying TK (TK-/-) or kinin B2 receptor (B2-/-)-deficient mice on different Ca diets. On a 0.9% wt/wt Ca diet, 129Sv or C57Bl/6 TK-/- mice excreted significantly more Ca in urine than their wild-type (WT) littermates. There was no difference between TK-/- and WT mice for plasma concentrations of Ca, Mg, creatinine, parathyroid hormone, or 1,25-dihydroxyvitamin D. On a low Ca (LCa) diet (0.01% wt/wt), urinary Ca excretion decreased in both TK-/- and WT mice but still remained higher in TK-/- mice compared with WT. The plasma Ca concentration was unchanged in C57Bl/6 TK-/- mice but decreased significantly in 129Sv TK-/- mice. Taken together, these data demonstrate that TK deficiency led to impaired RTCa absorption. On the LCa diet, renal TK gene expression doubled in WT mice. No change in urinary Ca excretion was observed in B2-/- mice, even after treatment with a kinin B1-receptor antagonist, and these mice adapted normally to the LCa diet. TK deficiency had no effect on the renal abundance of distal Ca transporter mRNA. These data suggest that TK may be a physiologic regulator of RTCa transport, acting through a non-kinin-mediated mechanism.

Analysis of Variance↗

PubMed2005

Molecular identification of Sch28080-sensitive K-ATPase activities in the mouse kidney.

Rat collecting ducts display either an ouabain-insensitive or an ouabain-sensitive K-ATPase activity inhibited by Sch28080 according as animals are fed a normal or a potassium-depleted diet (types I and III K-ATPase, respectively). Two isoforms of H,K-ATPase have been cloned from rat gastric mucosa and colon, respectively. Gastric and colonic H,K-ATPase are expressed in the kidney, suggesting that they might account for types I and III K-ATPases. However, this hypothesis is not fully supported by segmental expression of gastric and colonic H,K-ATPase along the rat collecting duct, as well as by comparison of the pharmacological properties of gastric and colonic H,K-ATPase expressed in Xenopus ovocyte and types I and III K-ATPases in rat collecting ducts. The aim of the present work is to address directly the molecular origin of types I and III K-ATPases in the mouse collecting duct by measuring K-ATPase activities in collecting ducts of wild-type mice and mice genetically deficient in either gastric or colonic H,K-ATPase fed either a regular or a potassium-depleted diet. Like the rat, mouse collecting ducts display type I or III K-ATPase activity when fed a regular or a potassium-depleted diet, respectively. Type I K-ATPase activity is detected in colonic H,K-ATPase-deficient mice but not in gastric H,K-ATPase-deficient animals. Conversely, type III K-ATPase activity disappears in colonic H,K-ATPase-deficient but not in gastric H,K-ATPase-deficient mice. In conclusion, types I and III K-ATPases measured in collecting ducts of normal and potassium-depleted mice reflect the functional expression of gastric and colonic H,K-ATPase, respectively.

Animals↗

PubMed2005

Links between dietary salt intake, renal salt handling, blood pressure, and cardiovascular diseases.

Epidemiological, migration, intervention, and genetic studies in humans and animals provide very strong evidence of a causal link between high salt intake and high blood pressure. The mechanisms by which dietary salt increases arterial pressure are not fully understood, but they seem related to the inability of the kidneys to excrete large amounts of salt. From an evolutionary viewpoint, the human species is adapted to ingest and excrete <1 g of salt per day, at least 10 times less than the average values currently observed in industrialized and urbanized countries. Independent of the rise in blood pressure, dietary salt also increases cardiac left ventricular mass, arterial thickness and stiffness, the incidence of strokes, and the severity of cardiac failure. Thus chronic exposure to a high-salt diet appears to be a major factor involved in the frequent occurrence of hypertension and cardiovascular diseases in human populations.

Animals↗

PubMed2004

Inactivation of the Na-Cl co-transporter (NCC) gene is associated with high BMD through both renal and bone mechanisms: analysis of patients with Gitelman syndrome and Ncc null mice.

UNLABELLED: Chronic thiazide treatment is associated with high BMD. We report that patients and mice with null mutations in the thiazide-sensitive NaCl cotransporter (NCC) have higher renal tubular Ca reabsorption, higher BMD, and lower bone remodeling than controls, as well as abnormalities in Ca metabolism, mainly caused by Mg depletion. INTRODUCTION: Chronic thiazide treatment decreases urinary Ca excretion (UVCa) and increases BMD. To understand the underlying mechanisms, Ca and bone metabolism were studied in two models of genetic inactivation of the thiazide-sensitive NaCl cotransporter (NCC): patients with Gitelman syndrome (GS) and Ncc knockout (Ncc(-/-)) mice. MATERIALS AND METHODS: Ca metabolism was analyzed in GS patients and Ncc(-/-) mice under conditions of low dietary Ca. BMD was measured by DXA in patients and mice, and bone histomorphometry was analyzed in mice. RESULTS: GS patients had low plasma Mg. They exhibited reduced UVCa, but similar serum Ca and GFR as control subjects, suggesting increased renal Ca reabsorption. Blood PTH was lower despite lower serum ionized Ca, and Mg repletion almost corrected both relative hypoparathyroidism and low UVCa. BMD was significantly increased in GS patients at both lumbar (+7%) and femoral (+16%) sites, and osteocalcin was reduced. In Ncc(-/-) mice, serum Ca and GFR were unchanged, but UVCa was reduced and PTH was elevated; Mg repletion largely corrected both abnormalities. Trabecular and cortical BMD were higher than in Ncc(+/+) mice (+4% and +5%, respectively), and despite elevated PTH, were associated with higher cortical thickness and lower endosteal osteoclastic surface. CONCLUSIONS: Higher BMD is observed in GS patients and Ncc(-/-) mice. Relative hypoparathyroidism (human) and bone resistance to PTH (mice), mainly caused by Mg depletion, can explain the low bone remodeling and normal/low serum Ca despite increased renal Ca reabsorption.

Adolescent↗

PubMed2004

The sequential cleavage of membrane anchored pro-EGF requires a membrane serine protease other than kallikrein in rat kidney.

Epidermal growth factor (EGF) is present in kidney membranes as an integral type I precursor protein, enzymatically processed to release immunoreactive materials in urine or incubation medium. The aim of this work was the elucidation of both the anchor of the serine protease activity that processes pro-EGF, and the determination of the steps of the enzymatic processing. Quantification of EGF containing molecules by RIA following gel filtration analysis demonstrated that the membrane precursor is first shed from the kidney membrane principally into a 170-kDa soluble precursor. This entire ectodomain is further processed into a 70-kDa precursor and finally into the mature 5.9 kDa urinary EGF. These species correspond to the ones found in urines. Both shedding and maturation events are clearly realized by membrane anchored serine protease activity, which remains active in detergent. By use of wild-type and knockout mice urines, we found that tissue kallikrein (TK) was not involved in the regulation of this processing.

Amino Acid Sequence↗

PubMed2004

Proximal renal tubular acidosis in TASK2 K+ channel-deficient mice reveals a mechanism for stabilizing bicarbonate transport.

The acid- and volume-sensitive TASK2 K+ channel is strongly expressed in renal proximal tubules and papillary collecting ducts. This study was aimed at investigating the role of TASK2 in renal bicarbonate reabsorption by using the task2 -/- mouse as a model. After backcross to C57BL6, task2 -/- mice showed an increased perinatal mortality and, in adulthood, a reduced body weight and arterial blood pressure. Patch-clamp experiments on proximal tubular cells indicated that TASK2 was activated during HCO3- transport. In control inulin clearance measurements, task2 -/- mice showed normal NaCl and water excretion. During i.v. NaHCO3 perfusion, however, renal Na+ and water reabsorption capacity was reduced in -/- animals. In conscious task2 -/- mice, blood pH, HCO3- concentration, and systemic base excess were reduced but urinary pH and HCO3- were increased. These data suggest that task2 -/- mice exhibit metabolic acidosis caused by renal loss of HCO3-. Both in vitro and in vivo results demonstrate the specific coupling of TASK2 activity to HCO3- transport through external alkalinization. The consequences of the task2 gene inactivation in mice are reminiscent of the clinical manifestations seen in human proximal renal tubular acidosis syndrome.

Acidosis, Renal Tubular↗

PubMed2004

Flow-dependent dilation mediated by endogenous kinins requires angiotensin AT2 receptors.

The vascular kallikrein-kinin system contributes to about one third of flow-dependent dilation in mice carotid arteries, by activating bradykinin B2 receptors coupled to endothelial nitric oxide (NO) release. Because the bradykinin/NO pathway may mediate some of the effects of angiotensin II AT2 receptors, we examined the possible contribution of AT2 receptors to the kinin-dependent response to flow. Changes in outer diameter after increases in flow rate were evaluated in perfused arteries from wild-type animals (TK+/+) and in tissue kallikrein-deficient mice (TK-/-) in which the presence of AT2 receptor expression was verified. Saralasin, a nonselective angiotensin II receptor antagonist, impaired significantly flow-induced dilation in TK+/+, whereas it had no effect in TK-/- mice. In both groups, blockade of AT1 receptors with losartan or candesartan did not affect the response to flow. Inhibition of AT2 receptors with PD123319 reduced significantly flow-induced dilation in TK+/+ mice, but had no significant effect in TK-/- mice. Combining PD123319 with the bradykinin B2 receptor antagonist HOE-140 had no additional effect to AT2 receptor blockade alone in TK+/+ arteries. Flow-dependent-dilation was also impaired in AT2 receptor deficient mice (AT2-/-) when compared with wild-type littermates. Furthermore, HOE-140 significantly reduced the response to flow in the AT2+/+, but not in AT2-/- mice. In conclusion, this study demonstrates that the presence of functional AT2 receptors is necessary to observe the contribution of the vascular kinin-kallikrein system to flow-dependent dilation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2004

Protective effects of high dietary potassium: nutritional and metabolic aspects.

Potassium (K+) requirements have been largely overlooked because severe deficiencies are uncommon due to the ubiquity of this element in foods. However, a transition toward modern ("Westernized") diets has led to a substantial decline of K+ intake compared with traditional food habits, and a large fraction of the population might now have suboptimal K+ intake. A high K+ intake was demonstrated to have protective effects against several pathologic states affecting the cardiovascular system, kidneys, and bones. Additionally, fruits and vegetables contain K/organic anion salts (malate, citrate), which exert alkalinizing effects, through KHCO(3)(-) generation, which serves to neutralize fixed acidity in urine. Low-grade metabolic acidosis, when not properly controlled, may exacerbate various catabolic processes (bone Ca++ mobilization, proteolysis), especially in the elderly. Fruits and vegetables are therefore receiving great attention in a strategy to increase the nutritional value of meals while reducing energy density and intake. The need to ensure a 2.5- to 3.5-g daily K+ supply from fruits and vegetables represents a strong rationale for the "5-10 servings per day" recommendations.

Acid-Base Equilibrium↗

PubMed2004

Role of tissue kallikrein in response to flow in mouse resistance arteries.

BACKGROUND: Tissue kallikrein, an essential enzyme in the formation of vascular kinins, contributes to flow-dependent dilatation (FDD) in large arteries. We hypothesized that the vascular kinin-kallikrein system may be involved in shear stress signalling in small resistance arteries, which have a key role in the systemic regulation of blood pressure. OBJECTIVE: To investigate the role of the vascular kallikrein-kinin system in mesenteric resistance arteries of mice during acute changes in blood flow. DESIGN: Arteries from wild-type mice (TK) and mice lacking tissue kallikrein (TK) were mounted in an arteriograph for the recording of changes in outer diameter during step increases in flow rate. RESULTS: Responses to phenylephrine, acetylcholine or sodium nitroprusside were not different between the two strains. FDD was significantly reduced in arteries of TK mice compared with that in mesenteric arteries of TK mice exposed to phenylephrine (P = 0.04). FDD was no longer different between TK and TK mice when experiments were performed in the presence of the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (l-NAME; P = 0.26), l-NAME plus diclofenac (P = 0.73), or l-NAME plus diclofenac plus potassium chloride (P = 0.31), indicating that inactivation of tissue kallikrein preferentially affects the contribution of nitric oxide to flow response. However, expression of endothelial NOS was comparable between TK and TK mesenteric arteries. Finally, the bradykinin B2 receptor antagonist, HOE-140, significantly decreased FDD in TK but not in TK arteries (P = 0.03 and P = 0.82, respectively). CONCLUSION: These results demonstrate the specific role of the tissue kallikrein in flow-induced dilatation, which is mediated by nitric oxide and bradykinin B2 receptor activation in resistance arteries.

Acetylcholine↗

PubMed2004

Altered renal distal tubule structure and renal Na(+) and Ca(2+) handling in a mouse model for Gitelman's syndrome.

Gitelman's syndrome, an autosomal recessive renal tubulopathy caused by loss-of-function mutations in the thiazide-sensitive NaCl co-transporter (NCC) of the distal convoluted tubule (DCT), is characterized by mild renal Na(+) wasting, hypocalciuria, hypomagnesemia, and hypokalemic alkalosis. For gaining further insights into the pathophysiology of Gitelman's syndrome, the impact of NCC ablation on the morphology of the distal tubule, on the distribution and abundance of ion transport proteins along its length, and on renal tubular Na(+) and Ca(2+) handling in a gene-targeted mouse model was studied. NCC-deficient mice had significantly elevated plasma aldosterone levels and exhibited hypocalciuria, hypomagnesemia, and compensated alkalosis. Immunofluorescent detection of distal tubule marker proteins and ultrastructural analysis revealed that the early DCT, which physiologically lacks epithelial Na(+) (ENaC) and Ca(2+) (TRPV5) channels, was virtually absent in NCC-deficient mice. In contrast, the late DCT seemed intact and retained expression of the apical ENaC and TRPV5 as well as basolateral Na(+)-Ca(2+) exchanger. The connecting tubule exhibited a marked epithelial hypertrophy accompanied by an increased apical abundance of ENaC. Ca(2+) reabsorption seemed unaltered in the distal convolution (i.e., the DCT and connecting tubule) as indicated by real-time reverse transcription-PCR, Western blotting, and immunohistochemistry for TRPV5 and Na(+)-Ca(2+) exchanger and micropuncture experiments. The last experiments further indicated that reduced glomerular filtration and enhanced fractional reabsorption of Na(+) and Ca(2+) upstream and of Na(+) downstream of the DCT provide some compensation for the Na(+) transport defect in the DCT and contribute to the hypocalciuria. Thus, loss of NCC leads to major structural remodeling of the renal distal tubule that goes along with marked changes in glomerular and tubular function, which may explain some of the clinical features of Gitelman's syndrome.

Alkalosis↗

PubMed2004

Arterial stiffness and angiotensinogen gene in hypertensive patients and mutant mice.

OBJECTIVE: To determine whether carotid artery stiffness was increased in patients with untreated essential hypertension who are homozygous for the T allele of the M235T polymorphism of the angiotensinogen (AGT) gene and in mutant mice carrying three copies of the angiotensinogen (Agt) gene. METHODS: Using echotracking systems, we studied carotid mechanical properties in 98 never-treated hypertensive patients according to their AGT genotype, and in Agt mutant mice. RESULTS: Patients homozygous for the T allele had a reduced carotid distensibility and an increased stiffness of the carotid wall material (Young's elastic modulus), independent of blood pressure, compared with patients homozygous for the M allele. In Agt1/2 mice, carotid distensibility was not significantly different from that of Agt1/1 (wild-type). Moreover, the stiffness of the arterial wall material was lower in Agt1/2 mice than in wild-type mice. In Agt1/2 mice, the greater blood pressure was not associated with arterial hypertrophy, resulting in a greater circumferential wall stress. The in-vivo and in-vitro pressor responses to angiotensin II were reduced in Agt1/2 mice, whereas the contractile response to phenylephrine was not significantly different between Agt1/1 and Agt1/2 mice, indicating the integrity of the contractile apparatus and suggesting a dysfunction of the angiotensin II type 1 receptor signalling pathways in Agt1/2 mice. CONCLUSION: These data suggest that the angiotensinogen TT genotype at position 235 could be a genetic marker for arterial stiffness in patients with never-treated hypertension, whereas in Agt1/2 mice the dysfunction of the angiotensin II type 1 receptor signalling pathways could explain the lack of arterial wall hypertrophy and stiffness.

Adult↗

PubMed2004

Sodium and potassium handling by the aldosterone-sensitive distal nephron: the pivotal role of the distal and connecting tubule.

Sodium reabsorption and potassium secretion in the distal convoluted tubule and in the connecting tubule can maintain the homeostasis of the body, especially when dietary sodium intake is high and potassium intake is low. Under these conditions, a large proportion of the aldosterone-regulated sodium and potassium transport would occur in these nephron segments before the tubular fluid reaches the collecting duct. The differences between these two segments and the collecting duct would be more quantitative than qualitative. The collecting duct would come into play when the upstream segments are overloaded by a primary genetic defect that affects sodium and/or potassium transport or by a diet that is exceedingly poor in sodium and rich in potassium. It is likely that the homeostatic role of the distal convoluted and connecting tubules, which are technically difficult to study, has been underestimated, whereas the role of the more easily accessible collecting duct may have been overemphasized.

Aldosterone↗

PubMed2003

Uterine artery structural and functional changes during pregnancy in tissue kallikrein-deficient mice.

OBJECTIVE: Tissue kallikrein (TK) participates in acute flow-induced dilatation (FID) of large arteries. We investigated whether TK deficiency blunts FID and alters chronic flow-related arterial structural and functional changes in resistance-sized muscular arteries. METHODS AND RESULTS: Vasomotor responses and structural parameters were determined in uterine arteries isolated from nonpregnant, 18- to 19-day pregnant, and 7-day postpartum TK-/- and TK+/+ littermate mice. In TK-/- mice, values of diameter, medial cross-sectional area (CSA), myogenic tone, and dilatation in response to acetylcholine were comparable to those values in TK+/+ mice, but FID (0 to 100 microL/min) was significantly reduced (55+/-4% versus 85+/-4% in TK+/+ mice). In both mouse strains, pregnancy resulted in significant increases in diameter and medial CSA and in the Nw-nitro-l-arginine methyl ester-sensitive component of FID. By 7 days after pregnancy, uterine arterial diameter and CSA values no longer differed from nonpregnant values, and FID was markedly reduced in TK-/- and TK+/+ mice. CONCLUSIONS: These observations (1) confirm at the level of resistance arteries the key role of TK in FID and (2) indicate that TK deficiency does not compromise arterial remodeling and changes in the contribution of NO to FID during and after pregnancy.

Animals↗

PubMed2003

Transforming growth factor beta in cardiovascular development and function.

Transforming growth factor betas (TGFbetas) are pleiotropic cytokines involved in many biological processes. Genetic engineering and tissue explanation studies have revealed specific non-overlapping roles for TGFbeta ligands and their signaling molecules in development and in normal function of the cardiovascular system in the adult. In the embryo, TGFbetas appear to be involved in epithelial-mesenchymal transformations (EMT) during endocardial cushion formation, and in epicardial epithelial-mesenchymal transformations essential for coronary vasculature, ventricular myocardial development and compaction. In the adult, TGFbetas are involved in cardiac hypertrophy, vascular remodeling and regulation of the renal renin-angiotensin system. The evidence for TGFbeta activities during cardiovascular development and physiologic function will be given and areas which need further investigation will be discussed.

Animals↗