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1.
Isenberg JS Ridnour LA Dimitry J Frazier WA Wink DA Roberts DD 《The Journal of biological chemistry》2006,281(36):26069-26080
CD36 is necessary for inhibition of some angiogenic responses by the matricellular glycoprotein thrombospondin-1 and is therefore assumed to be the receptor that mediates its anti-angiogenic activities. Although ligation of CD36 by antibodies, recombinant type 1 repeats of thrombospondin-1, or CD36-binding peptides was sufficient to inhibit nitric oxide (NO)-stimulated responses in both endothelial and vascular smooth muscle cells, picomolar concentrations of native thrombospondin-1 similarly inhibited NO signaling in vascular cells from wild-type and CD36-null mice. Ligation of the thrombospondin-1 receptor CD47 by recombinant C-terminal regions of thrombospondin-1, thrombospondin-1 peptides, or CD47 antibodies was also sufficient to inhibit NO-stimulated phenotypic responses and cGMP signaling in vascular cells. Thrombospondin-1 did not inhibit NO signaling in CD47-null vascular cells or NO-stimulated vascular outgrowth from CD47-null muscle explants in three-dimensional cultures. Furthermore, the CD36-binding domain of thrombospondin-1 and anti-angiogenic peptides derived from this domain failed to inhibit NO signaling in CD47-null cells. Therefore, ligation of either CD36 or CD47 is sufficient to inhibit NO-stimulated vascular cell responses and cGMP signaling, but only CD47 is necessary for this activity of thrombospondin-1 at physiological concentrations. 相似文献
2.
3.
Jeff S. Isenberg Douglas S. Annis Michael L. Pendrak Malgorzata Ptaszynska William A. Frazier Deane F. Mosher David D. Roberts 《The Journal of biological chemistry》2009,284(2):1116-1125
Thrombospondin-1 regulates nitric oxide (NO) signaling in vascular cells
via CD47. Because CD47 binding motifs are conserved in the C-terminal
signature domains of all five thrombospondins and indirect evidence has
implied CD47 interactions with other family members, we compared activities of
recombinant signature domains of thrombospondin-1, -2, and -4 to interact with
CD47 and modulate cGMP signaling. Signature domains of thrombospondin-2 and -4
were less active than that of thrombospondin-1 for inhibiting binding of
radiolabeled signature domain of thrombospondin-1 or SIRPα
(signal-regulatory protein) to cells expressing CD47. Consistent with this
binding selectivity, the signature domain of thrombospondin-1 was more potent
than those of thrombospondin-2 or -4 for inhibiting NO-stimulated cGMP
synthesis in vascular smooth muscle cells and downstream effects on cell
adhesion. In contrast to thrombospondin-1- and CD47-null cells, primary
vascular cells from thrombospondin-2-null mice lack enhanced basal and
NO-stimulated cGMP signaling. Effects of endogenous thrombospondin-2 on
NO/cGMP signaling could be detected only in thrombospondin-1-null cells.
Furthermore, tissue survival of ischemic injury and acute recovery of blood
flow in thrombospondin-2-nulls resembles that of wild type mice. Therefore,
thrombospondin-1 is the dominant regulator of NO/cGMP signaling via CD47, and
its limiting role in acute ischemic injury responses is not shared by
thrombospondin-2.Nitric oxide (NO) is a major mediator of intracellular and paracellular
signal transduction. NO preserves vascular health by minimizing the adhesion
of inflammatory cells to the vessel wall, limiting platelet activation, and
increasing blood vessel diameter and blood flow by relaxing vascular smooth
muscle cells (VSMC).3
These actions of NO are mediated by activating soluble isoforms of guanylate
cyclase (sGC) to increase cGMP levels, resulting in downstream activation of
cGMP-dependent protein kinases and ion channels
(1).Physiological NO/cGMP signaling is limited by several phosphodiesterases
that degrade cGMP and by thrombospondin-1 (TSP). TSP1 is a secreted protein
that is produced by vascular and inflammatory cells that regulates cellular
behavior by engaging several cell surface receptors. Recently we reported that
TSP1 potently blocks NO-stimulated prosurvival responses in endothelial and
VSMC (2,
3). TSP1 also plays a role in
promoting platelet thrombus formation and hemostasis by antagonizing the
antithrombotic activity of NO
(4). In all of these vascular
cells, picomolar concentrations of TSP1 are sufficient to block NO-stimulated
fluxes in cGMP by engaging its receptor CD47
(5). Nanomolar concentrations
of TSP1 further inhibit the same signaling pathway by inhibiting CD36-mediated
uptake of myristate into vascular cells
(6). In vivo, mice
lacking TSP1 demonstrate elevated basal tissue cGMP levels and greater
increases in regional blood flow in response to a NO challenge than wild type
controls (4). After an ischemic
insult, the absence of TSP1 or CD47 in transgenic mice is associated with
better maintenance of tissue perfusion and enhanced tissue survival.
Similarly, targeting TSP1 or CD47 using function blocking antibodies enhances
ischemic tissue perfusion and survival in wild type mice and pigs
(7,
8).TSP1 belongs to a family of five secreted glycoproteins that share an
evolutionarily conserved C-terminal signature domain
(9). TSP1 and TSP2 form a
distinct subfamily of trimeric proteins that exhibit similar anti-angiogenic
activities for endothelial cells in vitro and activities in
vivo to block tumor growth. Despite their similarities in structure, TSP1
and TSP2 have markedly different expression patterns after tissue injury, with
TSP1 being immediately expressed and maximal at day 3, whereas TSP2 was not
expressed until day 7 and was maximal 10 days after injury
(10). In addition, large
amounts of TSP1 but not TSP2 are stored in platelet α-granules and
released into the wound environment. Polymorphisms in TSP1 and TSP2 have been
linked to altered risk of premature myocardial infarction
(11,
12). A 3′-untranslated
region polymorphism in TSP2 is also associated with type 2 diabetes in men
(13). The molecular basis for
these associations is unclear.Less is known about the roles of the pentameric TSP3–5 in vascular
cells. TSP3 and TSP5 (also known as cartilage oligomeric matrix protein)
appear to serve their primary functions in bone development
(14,
15). However, a polymorphism
in TSP4 is associated with premature myocardial infarcts in certain
populations (11,
16,
17). A proatherogenic activity
for the A387P variant of TSP4 was proposed based on its differential ability
to modulate proliferation of endothelial and VSMC
(18). Cardiovascular functions
of TSP4 may also be linked to the high expression of TSP4 in heart
(19) and its altered
expression in that tissue during hypertensive heart failure
(20).The C-terminal domain of TSP1 is sufficient to mediate CD47-dependent
inhibition of cGMP signaling
(5). Of the two CD47 binding
VVM motifs identified in this domain of TSP1, the first is conserved among all
five TSPs, suggesting that CD47 binding could be a universal attribute of this
family (21). Based on
structural evidence that the VVM motifs may not be accessible
(22,
23), however, conservation of
VVM motifs may not be sufficient to predict CD47 binding. Uncertainty
regarding the location of the CD47 binding site in the G domain of TSP1
therefore limits interpretation of the known sequence homology to predict CD47
binding to other TSP family members.Although CD47 recognition of other TSPs has not been demonstrated
experimentally, a local deficiency of inflammation-associated T cell apoptosis
shared by TSP1-, CD47-, and TSP2-null mice is consistent with this hypothesis
(24). Furthermore, a
21-residue peptide from the C-terminal domain of TSP4 was found to decrease
human umbilical vein endothelial cell proliferation similar to the CD47
binding peptides from TSP1, although it lacks the VVM motif and no interaction
with CD47 was demonstrated
(25).To directly address whether other TSP family members can inhibit NO
responses and signaling in vascular cells, we now compare binding of
recombinant signature domains of TSP1, TSP2, and TSP4 to cell surface CD47 and
inhibition of NO-stimulated cell responses and cGMP signaling by these
domains. We also compared acute tissue blood flow and perfusion responses to
ischemic challenge in TSP1 and TSP2-null mice and cGMP responses in primary
cultures of vascular cells isolated from these mice. These studies clearly
demonstrate that CD47 selectively interacts with TSP1 and that the signature
domains of TSP2 and TSP4 are less potent inhibitors of NO signaling in
vascular cells in vitro. Furthermore, we show that the role of TSP1
to acutely limit recovery from ischemic injury in vivo is not shared
by TSP2. 相似文献
4.
Elfaridah P. FrazierJeff S. Isenberg Sruti ShivaLei Zhao Paul SchlesingerJulie Dimitry Mones S. Abu-AsabMaria Tsokos David D. RobertsWilliam A. Frazier 《Matrix biology》2011,30(2):154-161
CD47, a receptor for thrombospondin-1, limits two important regulatory axes: nitric oxide-cGMP signaling and cAMP signaling, both of which can promote mitochondrial biogenesis. Electron microscopy revealed increased mitochondrial densities in skeletal muscle from both CD47 null and thrombospondin-1 null mice. We further assessed the mitochondria status of CD47-null vs WT mice. Quantitative RT-PCR of RNA extracted from tissues of 3 month old mice revealed dramatically elevated expression of mRNAs encoding mitochondrial proteins and PGC-1α in both fast and slow-twitch skeletal muscle from CD47-null mice, but modest to no elevation in other tissues. These observations were confirmed by Western blotting of mitochondrial proteins. Relative amounts of electron transport enzymes and ATP/O2 ratios of isolated mitochondria were not different between mitochondria from CD47-null and WT cells. Young CD47-null mice displayed enhanced treadmill endurance relative to WTs and CD47-null gastrocnemius had undergone fiber type switching to a slow-twitch pattern of myoglobin and myosin heavy chain expression. In 12 month old mice, both skeletal muscle mitochondrial volume density and endurance had decreased to wild type levels. Expression of myosin heavy chain isoforms and myoglobin also reverted to a fast twitch pattern in gastrocnemius. Both CD47 and TSP1 null mice are leaner than WTs, use less oxygen and produce less heat than WT mice. CD47-null cells produce substantially less reactive oxygen species than WT cells. These data indicate that loss of signaling from the TSP1-CD47 system promotes accumulation of normally functioning mitochondria in a tissue-specific and age-dependent fashion leading to enhanced physical performance, lower reactive oxygen species production and more efficient metabolism. 相似文献
5.
Tissue ischemia and ischemia–reperfusion (I/R) remain sources of cell and tissue death. Inability to restore blood flow and limit reperfusion injury represents a challenge in surgical tissue repair and transplantation. Nitric oxide (NO) is a central regulator of blood flow, reperfusion signaling and angiogenesis. De novo NO synthesis requires oxygen and is limited in ischemic vascular territories. Nitrite (NO2?) has been discovered to convert to NO via heme-based reduction during hypoxia, providing a NO synthase independent and oxygen-independent NO source. Furthermore, blockade of the matrix protein thrombospondin-1 (TSP1) or its receptor CD47 has been shown to promote downstream NO signaling via soluble guanylate cyclase (sGC) and cGMP-dependant kinase. We hypothesized that nitrite would provide an ischemic NO source that could be potentiated by TSP1–CD47 blockade enhancing ischemic tissue survival, blood flow and angiogenesis. Both low dose nitrite and direct blockade of TSP1–CD47 interaction using antibodies or gene silencing increased acute blood flow and late tissue survival in ischemic full thickness flaps. Nitrite and TSP1 blockade both enhanced in vitro and in vivo angiogenic responses. The nitrite effect could be abolished by inhibition of sGC and cGMP signaling. Potential therapeutic synergy was tested in a more severe ischemic flap model. We found that combined therapy with nitrite and TSP1–CD47 blockade enhanced flap perfusion, survival and angiogenesis to a greater extent than either agent alone, providing approximately 100% flap survival. These data provide a new therapeutic paradigm for hypoxic NO signaling through enhanced cGMP mediated by TSP1–CD47 blockade and nitrite delivery. 相似文献
6.
Thomas W. Miller Sukhbir Kaur Kelly Ivins-O'Keefe David D. Roberts 《Matrix biology》2013,32(6):316-324
Thrombospondin-1 is a potent suppressor of T cell activation via its receptor CD47. However, the precise mechanism for this inhibition remains unclear. Because H2S is an endogenous potentiator of T cell activation and is necessary for full T cell activation, we hypothesized that thrombospondin-1 signaling through CD47 inhibits T cell activation by antagonizing H2S signaling. Primary T cells from thrombospondin-1 null mice were more sensitive to H2S-dependent activation assessed by proliferation and induction of interleukin-2 and CD69 mRNAs. Exogenous thrombospondin-1 inhibited H2S responses in wild type and thrombospondin-1 null T cells but enhanced the same responses in CD47 null T cells. Fibronectin, which shares integrin and glycosaminoglycan binding properties with thrombospondin-1 but not CD47 binding, did not inhibit H2S signaling. A CD47-binding peptide derived from thrombospondin-1 inhibited H2S-induced activation, whereas two other functional sequences from thrombospondin-1 enhanced H2S signaling. Therefore, engaging CD47 is necessary and sufficient for thrombospondin-1 to inhibit H2S-dependent T cell activation. H2S stimulated T cell activation by potentiating MEK-dependent ERK phosphorylation, and thrombospondin-1 inhibited this signaling in a CD47-dependent manner. Thrombospondin-1 also limited activation-dependent T cell expression of the H2S biosynthetic enzymes cystathionine β-synthase and cystathionine γ-lyase, thereby limiting the autocrine role of H2S in T cell activation. Thus, thrombospondin-1 signaling through CD47 is the first identified endogenous inhibitor of H2S signaling and constitutes a novel mechanism that negatively regulates T cell activation. 相似文献
7.
Reddy PG Bhuyan DK Bhuyan KC 《Biochemical and biophysical research communications》1999,261(2):345-349
The angiotensin II (Ang II) type 1 receptor mediates various actions of Ang II, whereas the function of the type 2 (AT2) receptor is not well understood. In the mice lacking the gene encoding the AT2 receptor, the pressor response to Ang II was increased although the underlying mechanism is unknown. We tested the hypothesis that vasoconstrictor response is exaggerated in the AT2 receptor null mice. We measured hemodynamic parameters and evaluated systemic vascular resistance (SVR) in the anesthetized open-chest wild-type and AT2 receptor null mice. Ang II infusion caused dose-dependent increases in SVR in both strains, while the response was significantly higher at 0.5 microgram/kg Ang II in the AT2 receptor null mice (305 +/- 53% of baseline) than in the wild-type mice (179 +/- 27% of baseline). To investigate further the vascular contractility, we examined contraction of aortic rings in vitro. The contraction induced by 1 microM Ang II was increased in the AT2 receptor null mice compared with that in the wild-type mice (0.82 +/- 0.11 vs. 0.54 +/- 0.12 g). Ang II-induced contraction was still greater in the AT2 receptor null mice when calibrated by the maximum tension induced by 90 mM KCl. These data suggest that the AT2 receptor modulates vascular contractility, which may influence blood pressure. 相似文献
8.
Matricellular proteins play diverse roles in modulating cell behavior by engaging specific cell surface receptors and interacting with extracellular matrix proteins, secreted enzymes, and growth factors. Studies of such interactions involving thrombospondin-1 have revealed several physiological functions and roles in the pathogenesis of injury responses and cancer, but the relatively mild phenotypes of mice lacking thrombospondin-1 suggested that thrombospondin-1 would not be a central player that could be exploited therapeutically. Recent research focusing on signaling through its receptor CD47, however, has uncovered more critical roles for thrombospondin-1 in acute regulation of cardiovascular dynamics, hemostasis, immunity, and mitochondrial homeostasis. Several of these functions are mediated by potent and redundant inhibition of the canonical nitric oxide pathway. Conversely, elevated tissue thrombospondin-1 levels in major chronic diseases of aging may account for the deficient nitric oxide signaling that characterizes these diseases, and experimental therapeutics targeting CD47 show promise for treating such chronic diseases as well as acute stress conditions that are associated with elevated thrombospondin-1 expression. 相似文献
9.
《Matrix biology》2014
Cardiovascular homeostasis and health is maintained through the balanced interactions of cardiac generated blood flow and cross-talk between the cellular components that comprise blood vessels. Central to this cross-talk is endothelial generated nitric oxide (NO) that stimulates relaxation of the contractile vascular smooth muscle (VSMC) layer of blood vessels. In cardiovascular disease this balanced interaction is disrupted and NO signaling is lost. Work over the last several years indicates that regulation of NO is much more complex than previously believed. It is now apparent that the secreted protein thrombospondin-1 (TSP1), that is upregulated in cardiovascular disease and animal models of the same, on activating cell surface receptor CD47, redundantly inhibits NO production and NO signaling. This inhibitory event has implications for baseline and disease-related responses mediated by NO. Further work has identified that TSP1-CD47 signaling stimulates enzymatic reactive oxygen species (ROS) production to further limit blood flow and promote vascular disease. Herein consideration is given to the most recent discoveries in this regard which identify the TSP1-CD47 axis as a major proximate governor of cardiovascular health. 相似文献
10.
Li Z Iwai M Wu L Shiuchi T Jinno T Cui TX Horiuchi M 《American journal of physiology. Heart and circulatory physiology》2003,284(1):H116-H121
The effects of intracerebroventricular (ICV) injection of angiotensin II (ANG II) on blood pressure and water intake were examined with the use of ANG II receptor-deficient mice. ICV injection of ANG II increased systolic blood pressure in a dose-dependent manner in wild-type (WT) mice and ANG type 2 AT(2) receptor null (knockout) (AT(2)KO) mice; however, this increase was significantly greater in AT(2)KO mice than in WT mice. The pressor response to a central injection of ANG II in WT mice was inhibited by ICV preinjection of the selective AT(1) receptor blocker valsartan but exaggerated by the AT(2) receptor blocker PD-123319. ICV injection of ANG II also increased water intake. It was partly but significantly suppressed both in AT(2)KO and AT(1)aKO mice. Water intake in AT(2)/AT(1)aKO mice did not respond to ICV injection of ANG II. Both valsartan and PD-123319 partly inhibited water intake in WT mice. These results indicate an antagonistic action between central AT(1)a and AT(2) receptors in the regulation of blood pressure, but they act synergistically in the regulation of water intake induced by ANG II. 相似文献
11.
Littler CM Wehling CA Wick MJ Fagan KA Cool CD Messing RO Dempsey EC 《American journal of physiology. Lung cellular and molecular physiology》2005,289(6):L1083-L1093
Loss of PKC-epsilon limits the magnitude of acute hypoxic pulmonary vasoconstriction (HPV) in the mouse. Therefore, we hypothesized that loss of PKC-epsilon would decrease the contractile and/or structural response of the murine pulmonary circulation to chronic hypoxia (Hx). However, the pattern of lung vascular responses to chronic Hx may or may not be predicted by the acute HPV response. Adult PKC-epsilon wild-type (PKC-epsilon(+/+)), heterozygous null, and homozygous null (PKC-epsilon(-/-)) mice were exposed to normoxia or Hx for 5 wk. PKC-epsilon(-/-) mice actually had a greater increase in right ventricular (RV) systolic pressure, RV mass, and hematocrit in response to chronic Hx than PKC-epsilon(+/+) mice. In contrast to the augmented PA pressure and RV hypertrophy, pulmonary vascular remodeling was increased less than expected (i.e., equal to PKC-epsilon(+/+) mice) in both the proximal and distal PKC-epsilon(-/-) pulmonary vasculature. The contribution of increased vascular tone to this pulmonary hypertension (PHTN) was assessed by measuring the acute vasodilator response to nitric oxide (NO). Acute inhalation of NO reversed the increased PA pressure in hypoxic PKC-epsilon(-/-) mice, implying that the exaggerated PHTN may be due to a relative deficiency in nitric oxide synthase (NOS). Despite the higher PA pressure, chronic Hx stimulated less of an increase in lung endothelial (e) and inducible (i) NOS expression in PKC-epsilon(-/-) than PKC-epsilon(+/+) mice. In contrast, expression of nNOS in PKC-epsilon(+/+) mice decreased in response to chronic Hx, while lung levels in PKC-epsilon(-/-) mice remained unchanged. In summary, loss of PKC-epsilon results in increased vascular tone, but not pulmonary vascular remodeling in response to chronic Hx. Blunting of Hx-induced eNOS and iNOS expression may contribute to the increased vascular tone. PKC-epsilon appears to be an important signaling intermediate in the hypoxic regulation of each NOS isoform. 相似文献
12.
13.
Barazi HO Li Z Cashel JA Krutzsch HC Annis DS Mosher DF Roberts DD 《The Journal of biological chemistry》2002,277(45):42859-42866
We examined the regulation of alpha4beta1 integrin function in melanoma cells and T cells by ligands of CD47. A CD47 antibody (B6H12) that inhibited alphavbeta3-mediated adhesion of melanoma cells induced by CD47-binding peptides from thrombospondin-1 directly stimulated alpha4beta1-mediated adhesion of the same cells to vascular cell adhesion molecule-1 and N-terminal regions of thrombospondin-1 or thrombospondin-2. B6H12 also stimulated alpha4beta1- as well as alpha2beta1- and alpha5beta1-mediated adhesion of CD47-expressing T cells but not of CD47-deficient T cells. alpha4beta1 and CD47 co-purified as a detergent-stable complex on a CD47 antibody affinity column. CD47-binding peptides based on C-terminal sequences of thrombospondin-1 also specifically enhanced adhesion of melanoma cells and T cells to alpha4beta1 ligands. Unexpectedly, activation of alpha4beta1 function by the thrombospondin-1 CD47-binding peptides also occurred in CD47-deficient T cells. CD47-independent activation of alpha4beta1 required the Val-Val-Met (VVM) motif of the peptides and was sensitive to inhibition by pertussis toxin. These results indicate that activation of alpha4beta1 by the CD47 antibody B6H12 and by VVM peptides occurs by different mechanisms. The antibody directly activates a CD47-alpha4beta1 complex, whereas VVM peptides may target an unidentified Gi-linked receptor that regulates alpha4beta1. 相似文献
14.
Predescu D Predescu S Shimizu J Miyawaki-Shimizu K Malik AB 《American journal of physiology. Lung cellular and molecular physiology》2005,289(3):L371-L381
Basal vascular endothelial permeability is normally kept low in part by the restrictiveness of interendothelial junctions (IEJs). We investigated the possible role of nitric oxide (NO) in controlling IEJ integrity and thereby regulating basal vascular permeability. We determined the permeability of continuous endothelia in multiple murine vascular beds, including lung vasculature, of wild-type mice, endothelial nitric oxide synthase (eNOS) null mice, and mice treated with NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME). Light and electron microscopic studies revealed that L-NAME treatment resulted in IEJs opening within a few minutes with a widespread response within 30 min. We observed a 35% increase in transendothelial transport of albumin, using as tracer dinitrophenylated albumin in mouse lungs and other organs studied. To rule out the involvement of blood cells in the mechanism of increased endothelial permeability, vascular beds were flushed free of blood, treated with L-NAME, and perfused with the tracer. The open IEJs observed in these studies indicated a direct role for NO in preserving the normal structure of endothelial junctions. We also used the electron-opaque tracer lanthanum chloride to assess vascular permeability. Lanthanum chloride was presented by perfusion to various vascular beds of mice lacking NO. Open IEJs were seen only in capillary and venular endothelial segments of mice lacking NO, and there was a concomitant increase in vascular permeability to the tracer. Together, these data demonstrate that constitutive eNOS-derived NO is a crucial determinant of IEJ integrity and thus serves to maintain the low basal permeability of continuous endothelia. 相似文献
15.
Verlander JW Hong S Pech V Bailey JL Agazatian D Matthews SW Coffman TM Le T Inagami T Whitehill FM Weiner ID Farley DB Kim YH Wall SM 《American journal of physiology. Renal physiology》2011,301(6):F1314-F1325
Pendrin is an anion exchanger expressed in the apical regions of B and non-A, non-B intercalated cells. Since angiotensin II increases pendrin-mediated Cl(-) absorption in vitro, we asked whether angiotensin II increases pendrin expression in vivo and whether angiotensin-induced hypertension is pendrin dependent. While blood pressure was similar in pendrin null and wild-type mice under basal conditions, following 2 wk of angiotensin II administration blood pressure was 31 mmHg lower in pendrin null than in wild-type mice. Thus pendrin null mice have a blunted pressor response to angiotensin II. Further experiments explored the effect of angiotensin on pendrin expression. Angiotensin II administration shifted pendrin label from the subapical space to the apical plasma membrane, independent of aldosterone. To explore the role of the angiotensin receptors in this response, pendrin abundance and subcellular distribution were examined in wild-type, angiotensin type 1a (Agtr1a) and type 2 receptor (Agtr2) null mice given 7 days of a NaCl-restricted diet (< 0.02% NaCl). Some mice received an Agtr1 inhibitor (candesartan) or vehicle. Both Agtr1a gene ablation and Agtr1 inhibitors shifted pendrin label from the apical plasma membrane to the subapical space, independent of the Agtr2 or nitric oxide (NO). However, Agtr1 ablation reduced pendrin protein abundance through the Agtr2 and NO. Thus angiotensin II-induced hypertension is pendrin dependent. Angiotensin II acts through the Agtr1a to shift pendrin from the subapical space to the apical plasma membrane. This Agtr1 action may be blunted by the Agtr2, which acts through NO to reduce pendrin protein abundance. 相似文献
16.
Albinsson S Shakirova Y Rippe A Baumgarten M Rosengren BI Rippe C Hallmann R Hellstrand P Rippe B Swärd K 《American journal of physiology. Regulatory, integrative and comparative physiology》2007,293(3):R1222-R1231
Caveolin-1 (Cav-1) is essential for the morphology of membrane caveolae and exerts a negative influence on a number of signaling systems, including nitric oxide (NO) production and activity of the MAP kinase cascade. In the vascular system, ablation of caveolin-1 may thus be expected to cause arterial dilatation and increased vessel wall mass (remodeling). This was tested in Cav-1 knockout (KO) mice by a detailed morphometric and functional analysis of mesenteric resistance arteries, shown to lack caveolae. Quantitative morphometry revealed increased media thickness and media-to-lumen ratio in KO. Pressure-induced myogenic tone and flow-induced dilatation were decreased in KO arteries, but both were increased toward wild-type (WT) levels following NO synthase (NOS) inhibition. Isometric force recordings following NOS inhibition showed rightward shifts of passive and active length-force relationships in KO, and the force response to alpha(1)-adrenergic stimulation was increased. In contrast, media thickness and force response of the aorta were unaltered in KO vs. WT, whereas lumen diameter was increased. Mean arterial blood pressure during isoflurane anesthesia was not different in KO vs. WT, but greater fluctuation in blood pressure over time was noted. Following NOS inhibition, fluctuations disappeared and pressure increased twice as much in KO (38 +/- 6%) compared with WT (17 +/- 3%). Tracer-dilution experiments showed increased plasma volume in KO. We conclude that NO affects blood pressure more in Cav-1 KO than in WT mice and that restructuring of resistance vessels and an increased responsiveness to adrenergic stimulation compensate for a decreased tone in Cav-1 KO mice. 相似文献
17.
Isenberg JS Jia Y Fukuyama J Switzer CH Wink DA Roberts DD 《The Journal of biological chemistry》2007,282(21):15404-15415
Although CD36 is generally recognized to be an inhibitory signaling receptor for thrombospondin-1 (TSP1), the molecular mechanism for transduction of this signal remains unclear. Based on evidence that myristic acid and TSP1 each modulate endothelial cell nitric oxide signaling in a CD36-dependent manner, we examined the ability of TSP1 to modulate the fatty acid translocase activity of CD36. TSP1 and a CD36 antibody that mimics the activity of TSP1 inhibited myristate uptake. Recombinant TSP1 type 1 repeats were weakly inhibitory, but an anti-angiogenic peptide derived from this domain potently inhibited myristate uptake. This peptide also inhibited membrane translocation of the myristoylated CD36 signaling target Fyn and activation of Src family kinases. Myristate uptake stimulated cGMP synthesis via endothelial nitric-oxide synthase and soluble guanylyl cyclase. CD36 ligands blocked myristate-stimulated cGMP accumulation in proportion to their ability to inhibit myristate uptake. TSP1 also inhibited myristate-stimulated cGMP synthesis by engaging its receptor CD47. Myristate stimulated endothelial and vascular smooth muscle cell adhesion on type I collagen via the NO/cGMP pathway, and CD36 ligands that inhibit myristate uptake blocked this response. Therefore, the fatty acid translocase activity of CD36 elicits proangiogenic signaling in vascular cells, and TSP1 inhibits this response by simultaneously inhibiting fatty acid uptake via CD36 and downstream cGMP signaling via CD47. 相似文献
18.
Kincer JF Uittenbogaard A Dressman J Guerin TM Febbraio M Guo L Smart EJ 《The Journal of biological chemistry》2002,277(26):23525-23533
Numerous studies have implicated either the presence or absence of CD36 in the development of hypertension. In addition, hypercholesterolemia is associated with the loss of nitric oxide-induced vasodilation and the subsequent increase in blood pressure. In the current study, we tested the hypothesis that diet-induced hypercholesterolemia promotes the disruption of agonist-stimulated nitric oxide generation and vasodilation in a CD36-dependent manner. To test this, C57BL/6, apoE null, CD36 null, and apoE/CD36 null mice were maintained on chow or high fat diets. In contrast to apoE null mice fed a chow diet, apoE null mice fed a high fat diet did not respond to acetylcholine with a decrease in blood pressure. Caveolae isolated from in vivo vessels did not contain endothelial nitric-oxide synthase and were depleted of cholesterol. Age-matched apoE/CD36 null mice fed a chow or high fat diet responded to acetylcholine with a decrease in blood pressure. The mechanism underlying the vascular dysfunction was reversible because vessels isolated from apoE null high fat-fed mice regained responsiveness to acetylcholine when incubated with plasma obtained from chow-fed mice. Further analysis demonstrated that the plasma low density lipoprotein fraction was responsible for depleting caveolae of cholesterol, removing endothelial nitric-oxide synthase from caveolae, and preventing nitric oxide production. In addition, the pharmacological removal of caveola cholesterol with cyclodextrin mimicked the effects caused by the low density lipoprotein fraction. We conclude that the ablation of CD36 prevented the negative impact of hypercholesterolemia on agonist-stimulated nitric oxide-mediated vasodilation in apoE null mice. These studies provide a direct link between CD36 and the early events that underlie hypercholesterolemia-mediated hypertension and mechanistic linkages between CD36 function, nitric-oxide synthase activation, caveolae integrity, and blood pressure regulation. 相似文献
19.
Mattson DL Meister CJ 《American journal of physiology. Regulatory, integrative and comparative physiology》2005,289(4):R991-R997
Experiments in wild-type (WT; C57BL/6J) mice, endothelial nitric oxide synthase null mutant [eNOS(-/-)] mice, and neuronal NOS null mutant [nNOS(-/-)] mice were performed to determine which NOS isoform regulates renal cortical and medullary blood flow under basal conditions and during the infusion of ANG II. Inhibition of NOS with N(omega)-nitro-l-arginine methyl ester (l-NAME; 50 mg/kg iv) in Inactin-anesthetized WT and nNOS(-/-) mice increased arterial blood pressure by 28-31 mmHg and significantly decreased blood flow in the renal cortex (18-24%) and the renal medulla (13-18%). In contrast, blood pressure and renal cortical and medullary blood flow were unaltered after l-NAME administration to eNOS(-/-) mice, indicating that NO derived from eNOS regulates baseline vascular resistance in mice. In subsequent experiments, intravenous ANG II (20 ng x kg(-1) x min(-1)) significantly decreased renal cortical blood flow (by 15-25%) in WT, eNOS(-/-), nNOS(-/-), and WT mice treated with l-NAME. The infusion of ANG II, however, led to a significant increase in medullary blood flow (12-15%) in WT and eNOS(-/-) mice. The increase in medullary blood flow following ANG II infusion was not observed in nNOS(-/-) mice, in WT or eNOS(-/-) mice pretreated with l-NAME, or in WT mice administered the nNOS inhibitor 5-(1-imino-3-butenyl)-l-ornithine (1 mg x kg(-1) x h(-1)). These data demonstrate that NO from eNOS regulates baseline blood flow in the mouse renal cortex and medulla, while NO produced by nNOS mediates an increase in medullary blood flow in response to ANG II. 相似文献
20.
Grimbert P Bouguermouh S Baba N Nakajima T Allakhverdi Z Braun D Saito H Rubio M Delespesse G Sarfati M 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(6):3534-3541
Thymus-derived CD4+ CD25+ T regulatory cells (Tregs) are essential for the maintenance of self-tolerance. What critical factors and conditions are required for the extra-thymic development of Tregs remains an important question. In this study, we show that the anti-inflammatory extracellular matrix protein, thrombospondin-1, promoted the generation of human peripheral regulatory T cells through the ligation of one of its receptor, CD47. CD47 stimulation by mAb or a thrombospondin-1 peptide induced naive or memory CD4+ CD25- T cells to become suppressive. The latter expressed increased amounts of CTLA-4, OX40, GITR, and Foxp3 and inhibited autologous Th0, Th1, and Th2 cells. Their regulatory activity was contact dependent, TGF-beta independent, and partially circumvented by IL-2. This previously unknown mechanism to induce human peripheral Tregs in response to inflammation may participate to the limitation of collateral damage induced by exacerbated responses to self or foreign Ags and thus be relevant for therapeutic intervention in autoimmune diseases and transplantation. 相似文献