title: Reduced cardiac L-type Ca2+ current in Ca(V)beta2-/- embryos impairs cardiac development and contraction with secondary defects in vascular maturation.
abstract: Cardiac myocyte contraction depends on transmembrane L-type Ca2+ currents and the ensuing release of Ca2+ from the sarcoplasmic reticulum. Here we show that these L-type Ca2+ currents are essential for cardiac pump function in the mouse at developmental stages where the functional significance of the heart becomes imperative to blood flow and to the continuing growth and survival of the embryo. Disruption of the Ca(V)beta2 gene, which encodes for the predominant ancillary beta subunit of cardiac Ca2+ channels, resulted in diminished L-type Ca2+ currents in cardiomyocytes of embryonic day 9.5 (E9.5). This led to a functionally compromised heart, causing defective remodeling of intra- and extraembryonic blood vessels and embryonic death following E10.5. The defects in vascular remodeling were also observed when the Ca(V)beta2 gene was selectively targeted in cardiomyocytes, demonstrating that they are secondary to cardiac failure rather than a result of the lack of Ca(V)beta2 proteins in the vasculature. Partial rescue of the Ca2+ channel currents by a Ca2+ channel agonist significantly postponed embryonic death in Ca(V)beta2-/- mice. Taken together, these data strongly support the essential role of L-type Ca2+ channel activity in cardiomyocytes for normal heart development and function and that this is a prerequisite for proper maturation of the vasculature.
authors.affiliation: Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, 66421 Homburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Weissgerber
authors.forename: Brigitte
authors.initials: B
authors.lastname: Held
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.forename: Lars
authors.initials: L
authors.lastname: Kaestner
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.forename: Peter
authors.initials: P
authors.lastname: Lipp
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001808:Blood Vessels / Q000196:embryology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D002303:Cardiac Output, Low / Q000196:embryology; D004553:Electric Conductivity; D004622:Embryo, Mammalian / Q000502:physiology; D047108:Embryonic Development; D005313:Fetal Death / Q000517:prevention & control; D015870:Gene Expression / Q000502:physiology; D006321:Heart / Q000196:embryology*; D006339:Heart Rate / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics
chemical_list: D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; D020033:Protein Isoforms; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester