A critical developmental role for tgfbr2 in myogenic cell lineages is revealed in mice expressing SM22-Cre, not SMMHC-Cre

Frutkin, Andrew D.; Shi, Haikun; Otsuka, Goro; Leveén, Per; Karlsson, Stefán; Dichek, David A.

doi:10.1016/j.yjmcc.2006.06.067

Cited by 50 publications

(53 citation statements)

References 39 publications

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“…Mice lacking T␤RII specifically in VSMCs exhibited an aberrant phenotype later in development than the conventional T␤RII or ALK5 mutant mice, indicating that disruption of TGF␤ signalling in VSMCs is not responsible for the early phenotypes observed in either the T␤RII or ALK5 mutants. Moreover, it has been shown independently that homozygous deletion of T␤RII by SM22-Cre mice is embryonic lethal, confirming SM22-Cre mice as useful tools for deleting floxed alleles in a large proportion of VSMCs (Frutkin et al, 2006). Additionally, ALK5(D266A) knock-in mice showed that TGF␤-induced ALK1 signalling required TGF␤/ALK5-induced SMAD2 signalling in ECs; if it were not required, the mutant phenotype would have appeared later, similar to the VSMC deletion of ALK5 rather than to its EC deletion.…”

Section: T␤rii and Alk5 Signal In Yolk Sac Endothelial And Smooth Musmentioning

confidence: 77%

Compensatory signalling induced in the yolk sac vasculature by deletion of TGFβ receptors in mice

Carvalho

Itoh

Goumans

et al. 2007

Journal of Cell Science

113

121

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Vascular development depends on transforming growth factor β (TGFβ), but whether signalling of this protein is required for the development of endothelial cells (ECs), vascular smooth muscle cells (VSMCs) or both is unclear. To address this, we selectively deleted the type I (ALK5, TGFBR1) and type II (TβRII, TGFBR2) receptors in mice. Absence of either receptor in ECs resulted in vascular defects in the yolk sac, as seen in mice lacking receptors in all cells, causing embryonic lethality at embryonic day (E)10.5. Deletion of TβRII specifically in VSMCs also resulted in vascular defects in the yolk sac; however, these were observed at later stages of development, allowing the embryo to survive to E12.5. Because TGFβ can also signal in ECs via ALK1 (ACVRL1), we replaced ALK5 by a mutant defective in SMAD2 and SMAD3 (SMAD2/3) activation that retained the ability to transactivate ALK1. This again caused defects in the yolk sac vasculature with embryonic lethality at E10.5, demonstrating that TGFβ/ALK1 signalling in ECs cannot compensate for the lack of TGFβ/ALK5-induced SMAD2/3 signalling in vivo. Unexpectedly, SMAD2 phosphorylation and α-smooth muscle actin (SMAα, ACTA2) expression occurred in the yolk sacs of ALK5–/– embryos and ALK5–/– embryonic stem cells undergoing vasculogenesis, and these processes could be blocked by an ALK4 (ACVR1B)/ALK5 inhibitor. Together, the data show that ALK5 is required in ECs and VSMCs for yolk sac vasculogenesis; in the absence of ALK5, ALK4 mediates SMAD2 phosphorylation and consequently SMAα expression.

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Section: T␤rii and Alk5 Signal In Yolk Sac Endothelial And Smooth Musmentioning

confidence: 77%

Compensatory signalling induced in the yolk sac vasculature by deletion of TGFβ receptors in mice

Carvalho

Itoh

Goumans

et al. 2007

Journal of Cell Science

113

121

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“…Two SM-cre lines were used: one that expresses from the SM myosin heavy chain promoter (smαMHC-cre) 14 and another from the SM 22 promoter (sm22α-cre). 15 The resulting smMHCcre+ Kir6.1(+/flx) or sm22cre+ Kir6.1(+/flx) or both mice were crossed with Kir6.1(flx/flx) or Kir6.1(+/flx) mice to generate tissue-specific knockout of Kir6.1 in SM [smMHCcre+ Kir6.1(flx/flx) and sm22cre+ Kir6.1(flx/flx)] ( Figure 1A) and the relevant littermate controls. For the SM conditional lines the wild-type (WT) genotypes (including cre+ +/+ and cre− flx/ flx and +/flx mice) were analyzed.…”

Section: Characterization Of the Sm-specific Kir61 Knockout Mousementioning

confidence: 99%

The ATP-Sensitive Potassium Channel Subunit, Kir6.1, in Vascular Smooth Muscle Plays a Major Role in Blood Pressure Control

et al. 2014

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A TP-sensitive potassium channels (K ATP ) are widely expressed in a range of tissues, including brain, heart, pancreas, and smooth muscle (SM), where they are involved in the regulation of biological processes such as insulin release, vascular tone, and adaptation to stresses such as ischemia and hypoxia. They are activated by either declining ATP or increasing ADP concentrations or both, thus coupling intracellular metabolism to membrane excitability. 1 K ATP channels are composed of 4 pore-forming Kir6.x subunits (Kir6.1 or Kir6.2) and 4 large regulatory sulphonylurea receptor subunits (SUR1, SUR2A or SUR2B) to form a functional hetero-octomeric complex.1 The vascular SM K ATP channel is thought to be composed of the Kir6.1 and SUR2B subunits.2,3 These SM K ATP channels have been implicated in the regulation of vascular tone through their proposed involvement in the actions of vasoconstrictors and vasodilators. [4][5][6][7] The integrative physiological role of these channels has been investigated in mice with global genetic deletion of either Kir6.1 or SUR2. 8,9 The mice were hypertensive and prone to sudden death, which was attributed to coronary artery vasospasm because of the absence of K ATP currents in the SM of the coronary arteries. However, when SUR2B was specifically expressed in SM in SUR2 global knockout mice resulting in reconstitution of the K ATP current, the lethal phenotype persisted.10 Furthermore, transgenic expression of SUR2A in cardiomyocytes in SUR2 null mice led to a dramatic reduction in the degree and frequency of episodes of ST elevation on the ECG measured using telemetry.11 The implication was that reconstitution of K ATP in cardiac myocytes led to a reduction of coronary artery SM spasm and it was proposed that K ATP channels outside the SM cell (SMC) are critical in driving the vascular phenotype in the global knockout mice and that the vascular SM K ATP channel contributes modestly to vascular control. 10 A global genetic deletion of Kir6.1 or SUR2 is not selective for the SM channel and potentially channels in the endothelium, nervous system, and heart might all be affected. Here, using a new mouse model, we show that Kir6.1 is indeed the pore-forming subunit of the K ATP channel in vascular SM and that it has a central role in the regulation of blood pressure (BP).Abstract-ATP-sensitive potassium channels (K ATP ) regulate a range of biological activities by coupling membrane excitability to the cellular metabolic state. In particular, it has been proposed that K ATP channels and specifically, the channel subunits Kir6.1 and SUR2B, play an important role in the regulation of vascular tone. However, recent experiments have suggested that K ATP channels outside the vascular smooth muscle compartment are the key determinant of the observed behavior. Thus, we address the importance of the vascular smooth muscle K ATP channel, using a novel murine model in which it is possible to conditionally delete the Kir6.1 subunit.

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“…Although the SM-MHC promoter restricts the adult expression to SM (46), it is also active transiently during male gametogenesis (9,10,16), resulting in the recombination of NCX1 exon 11 in meiotic cells. Thus crosses of female NCX1…”

Section: Experimental Animalsmentioning

confidence: 99%

Knockout of Na⁺/Ca²⁺ exchanger in smooth muscle attenuates vasoconstriction and L-type Ca²⁺ channel current and lowers blood pressure

Zhang¹,

Ren²,

Chen

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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) and the NCX inhibitor, SEA0400, were used to study the physiological role of NCX1 in mouse mesenteric arteries. NCX1 protein expression was greatly reduced in arteries from NCX1 SMϪ/Ϫ mice generated with Cre recombinase. Mean blood pressure (BP) was 6 -10 mmHg lower in NCX1 SMϪ/Ϫ mice than in wild-type (WT) controls. Vasoconstriction was studied in isolated, pressurized mesenteric small arteries from WT and NCX1 SMϪ/Ϫ mice and in heterozygotes with a global null mutation (NCX1 Fx/Ϫ ). Reduced NCX1 activity was manifested by a marked attenuation of responses to low extracellular Na ϩ concentration, nanomolar ouabain, and SEA0400. Myogenic tone (MT, 70 mmHg) was reduced by ϳ15% in NCX1 SMϪ/Ϫ arteries and, to a similar extent, by SEA0400 in WT arteries. MT (21, 48). Moreover, the SM-specific overexpression of NCX elevates BP and induces salt-dependent hypertension, and SEA0400 lowers BP in several salt-dependent animal models (21). Indeed, NCX type-1 (NCX1) is upregulated in mesenteric arteries from rats with ouabain-induced hypertension (33) and pulmonary arteries from humans with primary pulmonary hypertension (49). Whether NCX is involved in maintaining normal BP, however, has not been resolved. Here we employ a SM-specific knockout approach to examine the role of NCX in arterial contractility and the maintenance of vascular tone and BP.Three isoforms of NCX have been identified: NCX1 is abundant in the heart and is ubiquitously expressed, whereas NCX2 and NCX3 are both restricted to brain and skeletal muscle (34). NCX1 is the only isoform present in ASMCs, where two splice variants, NCX1.3 and NCX1.7, are expressed (27,35). In cardiac myocytes, NCX1 makes a major contribution to Ca 2ϩ extrusion during diastole (3, 11). Nevertheless, cardiac-specific NCX1 knockout mice thrive: the loss of NCX1 is compensated by a reduced L-type voltage-gated Ca 2ϩ channel (LVGC) current and a shortened action potential because of accelerated Ca 2ϩ -dependent LVGC inactivation and augmented transient outward K ϩ current (18,31,32). Importantly, cardiac NCX1-mediated Ca 2ϩ flux must be inward during depolarization and systole (5). The situation is complicated, however, because exchanger-mediated fluxes depend on the relative activation of the exchanger, governed by cytosolic Na ϩ and Ca 2ϩ (26), as well as on the net driving force, governed by the membrane potential (V m ) and the Na ϩ and Ca 2ϩ electrochemical gradients (5

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A critical developmental role for tgfbr2 in myogenic cell lineages is revealed in mice expressing SM22-Cre, not SMMHC-Cre

Cited by 50 publications

References 39 publications

Compensatory signalling induced in the yolk sac vasculature by deletion of TGFβ receptors in mice

Compensatory signalling induced in the yolk sac vasculature by deletion of TGFβ receptors in mice

The ATP-Sensitive Potassium Channel Subunit, Kir6.1, in Vascular Smooth Muscle Plays a Major Role in Blood Pressure Control

Knockout of Na⁺/Ca²⁺ exchanger in smooth muscle attenuates vasoconstriction and L-type Ca²⁺ channel current and lowers blood pressure

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A critical developmental role for tgfbr2 in myogenic cell lineages is revealed in mice expressing SM22-Cre, not SMMHC-Cre

Cited by 50 publications

References 39 publications

Compensatory signalling induced in the yolk sac vasculature by deletion of TGFβ receptors in mice

Compensatory signalling induced in the yolk sac vasculature by deletion of TGFβ receptors in mice

The ATP-Sensitive Potassium Channel Subunit, Kir6.1, in Vascular Smooth Muscle Plays a Major Role in Blood Pressure Control

Knockout of Na+/Ca2+ exchanger in smooth muscle attenuates vasoconstriction and L-type Ca2+ channel current and lowers blood pressure

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Knockout of Na⁺/Ca²⁺ exchanger in smooth muscle attenuates vasoconstriction and L-type Ca²⁺ channel current and lowers blood pressure