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Thrombospondin-1 in early flow-related remodeling of mesenteric arteries from young normotensive and spontaneously hypertensive rats.

Lemkens P, Boari G, Fazzi G, Janssen G, Murphy-Ullrich J, Schiffers P, De Mey J - Open Cardiovasc Med J (2012)

Bottom Line: We tested the hypotheses that TSP-1 participates in the initiation of remodeling of small muscular arteries in response to altered blood flow and that the N-terminal domain of TSP-1 (hepI) can reverse the pathological inward remodeling of resistance arteries from SHR.We measured (1) changes in gene/protein expression in MA of 6 week old WKY and SHR exposed to either increased (+ 100 %) or reduced blood flow (- 90 %) for 24-40 hours and (2) structural changes in MA of 12 week old SHR exposed for 3 days to hepI in organ culture.In both HF and LF of WKY, mRNA expression of eNOS, sGCα1 and PKG1β were significantly reduced (p < 0.05), whereas mRNA of TSP1 was markedly increased (p < 0.05).In MA of young SHR, similar results were obtained except that eNOS mRNA was not reduced in LF.Expression of TSP1 protein was significantly increased in LF of young WKY and SHR (p < 0.05).

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

ABSTRACT
We tested the hypotheses that TSP-1 participates in the initiation of remodeling of small muscular arteries in response to altered blood flow and that the N-terminal domain of TSP-1 (hepI) can reverse the pathological inward remodeling of resistance arteries from SHR.We measured (1) changes in gene/protein expression in MA of 6 week old WKY and SHR exposed to either increased (+ 100 %) or reduced blood flow (- 90 %) for 24-40 hours and (2) structural changes in MA of 12 week old SHR exposed for 3 days to hepI in organ culture.In both HF and LF of WKY, mRNA expression of eNOS, sGCα1 and PKG1β were significantly reduced (p < 0.05), whereas mRNA of TSP1 was markedly increased (p < 0.05). In MA of young SHR, similar results were obtained except that eNOS mRNA was not reduced in LF. Expression of TSP1 protein was significantly increased in LF of young WKY and SHR (p < 0.05). Exposure of MA of 12 week old SHR to hepI (1 µmol/L) resulted in a rapid lumen diameter increase (+ 12 ± 2% after 3 days) without alteration in vascular reactivity, distensibility, media surface area or cell number.These are the first observations of reduced gene expression of eNOS/sGC/PKG and increased expression of TSP1 at the initiation of arterial remodeling in young WKY and SHR, irrespective of its outward or inward outcome. Furthermore, a fragment of TSP-1 rapidly and directly reversed pathological inward arterial remodeling of SHR in vitro.

No MeSH data available.


Related in: MedlinePlus

In vitro contractile reactivity of mesenteric small arteries of 6 week old WKY rats (panel A) and SHR rats (panel B) exposed tonormal flow (black bars) or for 32 hours to increased (hatched bars) or reduced blood flow (cross-hatched bars). Means ± SEM (n = 8-11).Normalized diameter and maximal contraction in response to 125 mmol/L K+ (top left) and the effect of indomethacin and L-NAME oncontractile responses to 40 mmol/L K+ (top right) are shown along with the relaxing responses to acetylcholine during K+-inducedcontraction in the presence of indomethacin (bottom left) and the relaxing responses to Na-nitroprusside during K+-induced contraction in thepresence of indomethacin and L-NAME (bottom right) for NF (closed circle), HF (open circle) and LF (closed triangle). *p<0.05 versus NF;#p<0.05 INDO versus INDO + L-NAME.
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Figure 2: In vitro contractile reactivity of mesenteric small arteries of 6 week old WKY rats (panel A) and SHR rats (panel B) exposed tonormal flow (black bars) or for 32 hours to increased (hatched bars) or reduced blood flow (cross-hatched bars). Means ± SEM (n = 8-11).Normalized diameter and maximal contraction in response to 125 mmol/L K+ (top left) and the effect of indomethacin and L-NAME oncontractile responses to 40 mmol/L K+ (top right) are shown along with the relaxing responses to acetylcholine during K+-inducedcontraction in the presence of indomethacin (bottom left) and the relaxing responses to Na-nitroprusside during K+-induced contraction in thepresence of indomethacin and L-NAME (bottom right) for NF (closed circle), HF (open circle) and LF (closed triangle). *p<0.05 versus NF;#p<0.05 INDO versus INDO + L-NAME.

Mentions: To evaluate potential functional consequences of the observed downregulation of the NO/sGC/PKG pathway, we recorded arterial contractile reactivity in vitro in MA of 6 week old WKY and SHR rats. At 24 hours after flow-modifying surgery there were no statistically significant differences between NF, HF or LF arteries (n = 4-6, data not shown). Because changes in the abundance and activity of proteins lag behind changes in mRNA expression, functional analyses were repeated at 32 hours after altered blood flow in vivo. These results are summarized in Fig. (2). The diameter of WKY LF arteries was significantly reduced which is consistent with the rapid inward remodeling of LF in vivo [14]. L-NAME significantly increased the contractile response to 40 mmol/L K+ in NF arteries of WKY and SHR. Relaxing responses of depolarized vessels to acetylcholine (in the presence of indomethacin) and to Na-nitroprusside (in the presence of indomethacin and L-NAME) did not differ between NF, HF or LF arteries (Fig. 2A). These findings indicate that the marked and concurrent reductions of the mRNA levels for eNOS, sGCα1 and PKG1β were not accompanied by reduced relaxing responses to basal and stimulated endothelium-derived or exogenous NO during initiation of outward (HF) or inward (LF) flow-related arterial remodeling in WKY. Similar results were obtained in SHR, as shown in Fig. (2B). In contrast to WKY, the diameter of SHR LF arteries did not differ from that of NF and HF arteries.


Thrombospondin-1 in early flow-related remodeling of mesenteric arteries from young normotensive and spontaneously hypertensive rats.

Lemkens P, Boari G, Fazzi G, Janssen G, Murphy-Ullrich J, Schiffers P, De Mey J - Open Cardiovasc Med J (2012)

In vitro contractile reactivity of mesenteric small arteries of 6 week old WKY rats (panel A) and SHR rats (panel B) exposed tonormal flow (black bars) or for 32 hours to increased (hatched bars) or reduced blood flow (cross-hatched bars). Means ± SEM (n = 8-11).Normalized diameter and maximal contraction in response to 125 mmol/L K+ (top left) and the effect of indomethacin and L-NAME oncontractile responses to 40 mmol/L K+ (top right) are shown along with the relaxing responses to acetylcholine during K+-inducedcontraction in the presence of indomethacin (bottom left) and the relaxing responses to Na-nitroprusside during K+-induced contraction in thepresence of indomethacin and L-NAME (bottom right) for NF (closed circle), HF (open circle) and LF (closed triangle). *p<0.05 versus NF;#p<0.05 INDO versus INDO + L-NAME.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3367304&req=5

Figure 2: In vitro contractile reactivity of mesenteric small arteries of 6 week old WKY rats (panel A) and SHR rats (panel B) exposed tonormal flow (black bars) or for 32 hours to increased (hatched bars) or reduced blood flow (cross-hatched bars). Means ± SEM (n = 8-11).Normalized diameter and maximal contraction in response to 125 mmol/L K+ (top left) and the effect of indomethacin and L-NAME oncontractile responses to 40 mmol/L K+ (top right) are shown along with the relaxing responses to acetylcholine during K+-inducedcontraction in the presence of indomethacin (bottom left) and the relaxing responses to Na-nitroprusside during K+-induced contraction in thepresence of indomethacin and L-NAME (bottom right) for NF (closed circle), HF (open circle) and LF (closed triangle). *p<0.05 versus NF;#p<0.05 INDO versus INDO + L-NAME.
Mentions: To evaluate potential functional consequences of the observed downregulation of the NO/sGC/PKG pathway, we recorded arterial contractile reactivity in vitro in MA of 6 week old WKY and SHR rats. At 24 hours after flow-modifying surgery there were no statistically significant differences between NF, HF or LF arteries (n = 4-6, data not shown). Because changes in the abundance and activity of proteins lag behind changes in mRNA expression, functional analyses were repeated at 32 hours after altered blood flow in vivo. These results are summarized in Fig. (2). The diameter of WKY LF arteries was significantly reduced which is consistent with the rapid inward remodeling of LF in vivo [14]. L-NAME significantly increased the contractile response to 40 mmol/L K+ in NF arteries of WKY and SHR. Relaxing responses of depolarized vessels to acetylcholine (in the presence of indomethacin) and to Na-nitroprusside (in the presence of indomethacin and L-NAME) did not differ between NF, HF or LF arteries (Fig. 2A). These findings indicate that the marked and concurrent reductions of the mRNA levels for eNOS, sGCα1 and PKG1β were not accompanied by reduced relaxing responses to basal and stimulated endothelium-derived or exogenous NO during initiation of outward (HF) or inward (LF) flow-related arterial remodeling in WKY. Similar results were obtained in SHR, as shown in Fig. (2B). In contrast to WKY, the diameter of SHR LF arteries did not differ from that of NF and HF arteries.

Bottom Line: We tested the hypotheses that TSP-1 participates in the initiation of remodeling of small muscular arteries in response to altered blood flow and that the N-terminal domain of TSP-1 (hepI) can reverse the pathological inward remodeling of resistance arteries from SHR.We measured (1) changes in gene/protein expression in MA of 6 week old WKY and SHR exposed to either increased (+ 100 %) or reduced blood flow (- 90 %) for 24-40 hours and (2) structural changes in MA of 12 week old SHR exposed for 3 days to hepI in organ culture.In both HF and LF of WKY, mRNA expression of eNOS, sGCα1 and PKG1β were significantly reduced (p < 0.05), whereas mRNA of TSP1 was markedly increased (p < 0.05).In MA of young SHR, similar results were obtained except that eNOS mRNA was not reduced in LF.Expression of TSP1 protein was significantly increased in LF of young WKY and SHR (p < 0.05).

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

ABSTRACT
We tested the hypotheses that TSP-1 participates in the initiation of remodeling of small muscular arteries in response to altered blood flow and that the N-terminal domain of TSP-1 (hepI) can reverse the pathological inward remodeling of resistance arteries from SHR.We measured (1) changes in gene/protein expression in MA of 6 week old WKY and SHR exposed to either increased (+ 100 %) or reduced blood flow (- 90 %) for 24-40 hours and (2) structural changes in MA of 12 week old SHR exposed for 3 days to hepI in organ culture.In both HF and LF of WKY, mRNA expression of eNOS, sGCα1 and PKG1β were significantly reduced (p < 0.05), whereas mRNA of TSP1 was markedly increased (p < 0.05). In MA of young SHR, similar results were obtained except that eNOS mRNA was not reduced in LF. Expression of TSP1 protein was significantly increased in LF of young WKY and SHR (p < 0.05). Exposure of MA of 12 week old SHR to hepI (1 µmol/L) resulted in a rapid lumen diameter increase (+ 12 ± 2% after 3 days) without alteration in vascular reactivity, distensibility, media surface area or cell number.These are the first observations of reduced gene expression of eNOS/sGC/PKG and increased expression of TSP1 at the initiation of arterial remodeling in young WKY and SHR, irrespective of its outward or inward outcome. Furthermore, a fragment of TSP-1 rapidly and directly reversed pathological inward arterial remodeling of SHR in vitro.

No MeSH data available.


Related in: MedlinePlus