RESUMO
OBJECTIVE: In resistance arteries, diameter adjustment in response to pressure changes depends on the vascular cytoskeleton integrity. Serum response factor (SRF) is a dispensable transcription factor for cellular growth, but its role remains unknown in resistance arteries. We hypothesized that SRF is required for appropriate microvascular contraction. METHODS AND RESULTS: We used mice in which SRF was specifically deleted in smooth muscle or endothelial cells, and their control. Myogenic tone and pharmacological contraction was determined in resistance arteries. mRNA and protein expression were assessed by quantitative real-time PCR (qRT-PCR) and Western blot. Actin polymerization was determined by confocal microscopy. Stress-activated channel activity was measured by patch clamp. Myogenic tone developing in response to pressure was dramatically decreased by SRF deletion (5.9±2.3%) compared with control (16.3±3.2%). This defect was accompanied by decreases in actin polymerization, filamin A, myosin light chain kinase and myosin light chain expression level, and stress-activated channel activity and sensitivity in response to pressure. Contractions induced by phenylephrine or U46619 were not modified, despite a higher sensitivity to p38 blockade; this highlights a compensatory pathway, allowing normal receptor-dependent contraction. CONCLUSIONS: This study shows for the first time that SRF has a major part to play in the control of local blood flow via its central role in pressure-induced myogenic tone in resistance arteries.
Assuntos
Pressão Arterial , Músculo Liso Vascular/metabolismo , Fator de Resposta Sérica/metabolismo , Cauda/irrigação sanguínea , Resistência Vascular , Vasodilatação , Actinas/metabolismo , Animais , Pressão Arterial/efeitos dos fármacos , Artérias/metabolismo , Western Blotting , Sinalização do Cálcio , Proteínas Contráteis/metabolismo , Relação Dose-Resposta a Droga , Filaminas , Regulação da Expressão Gênica , Masculino , Mecanotransdução Celular , Potenciais da Membrana , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Microscopia Confocal , Músculo Liso Vascular/efeitos dos fármacos , Miografia , Cadeias Leves de Miosina/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Técnicas de Patch-Clamp , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Resposta Sérica/deficiência , Fator de Resposta Sérica/genética , Fatores de Tempo , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Myxomatous dystrophy of the cardiac valves is a heterogeneous group of disorders, including syndromic diseases such as Marfan syndrome and isolated valvular diseases. Mitral valve prolapse, the most common form of this disease, is presumed to affect approximately 2% to 3% of the population and remains one of the most common causes of valvular surgery. During the past years, important effort has been made to better understand the pathophysiological basis of mitral valve prolapse. Autosomal-dominant transmission is the usual inheritance with reduced penetrance and variable expressivity. Three loci have been mapped to chromosomes 16p11-p12, 11p15.4 and 13q31-32, but the underlying genetic defects are not currently known. An X-linked recessive form has been originally described by Monteleone and Fagan in 1969. Starting from one large French family and three smaller other families in which MVP was transmitted with an X-linked pattern, we have been able to identify three filamin A mutations p.Gly288Arg and p.Val711Asp and a 1,944-bp genomic deletion coding for exons 16 to 19. In this review, we describe the genetic, echocardiographic and functional aspects of the filamin-A-related myxomatous mitral valve dystrophy.