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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

Effects of time (control, top left) and 1 µmol/L hepI (hepI, top right) on passive pressure-diameter relationships in mesenteric smallarteries (MA) of 12 week old SHR during organ culture. Calculated distensibility for control MA (day 0 and day 3, bottom left) and hepItreated MA (day 0 and day 3, bottom right). Values are shown as means ± SEM (n = 12). Closed circle, day 0; open circle, day 1; closedtriangle, day 2; open triangle, day 3. *p<0.05, versus day 0.
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Figure 4: Effects of time (control, top left) and 1 µmol/L hepI (hepI, top right) on passive pressure-diameter relationships in mesenteric smallarteries (MA) of 12 week old SHR during organ culture. Calculated distensibility for control MA (day 0 and day 3, bottom left) and hepItreated MA (day 0 and day 3, bottom right). Values are shown as means ± SEM (n = 12). Closed circle, day 0; open circle, day 1; closedtriangle, day 2; open triangle, day 3. *p<0.05, versus day 0.

Mentions: To evaluate structural consequences of upregulated TSP1 mRNA and protein expression, isolated arteries were exposed to hepI under constant conditions of pressure (80 mmHg) and flow (no flow) in vitro. These experiments were deliberately performed in arteries of 12 week old SHR that display an inward eutrophic remodeling which contributes to the increased peripheral resistance and blood pressure [24, 29]. In the untreated arteries, the diameter at 80 mmHg and the relationship between passive diameter and transmural pressure did not change during the 3 day culture period (Fig. 4). The presence of 1 μmol/L hepI, however, resulted in an increase of the diameter at 80 mmHg and in an upward shift of the pressure-diameter curves (p < 0.05 for day 1, day 2 and day 3)(Fig. 4). Arterial structural diameter was increased by 7.5 ± 1.9 % within 24 hours and increased further to +12.6 ± 2.4 % after 3 days (Fig. 4). Exposure to hepI did not modify calculated distensibility (Fig. 4), general arterial histology (not shown), and did not result in statistically significant changes in media cross sectional area (13693 ± 4043 μm2 versus 12881 ± 3182 μm2) or cell number (52 ± 11 versus 54 ± 8 nuclear profiles/section) indicating that the hepI-induced outward remodeling was eutrophic in nature.


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)

Effects of time (control, top left) and 1 µmol/L hepI (hepI, top right) on passive pressure-diameter relationships in mesenteric smallarteries (MA) of 12 week old SHR during organ culture. Calculated distensibility for control MA (day 0 and day 3, bottom left) and hepItreated MA (day 0 and day 3, bottom right). Values are shown as means ± SEM (n = 12). Closed circle, day 0; open circle, day 1; closedtriangle, day 2; open triangle, day 3. *p<0.05, versus day 0.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Effects of time (control, top left) and 1 µmol/L hepI (hepI, top right) on passive pressure-diameter relationships in mesenteric smallarteries (MA) of 12 week old SHR during organ culture. Calculated distensibility for control MA (day 0 and day 3, bottom left) and hepItreated MA (day 0 and day 3, bottom right). Values are shown as means ± SEM (n = 12). Closed circle, day 0; open circle, day 1; closedtriangle, day 2; open triangle, day 3. *p<0.05, versus day 0.
Mentions: To evaluate structural consequences of upregulated TSP1 mRNA and protein expression, isolated arteries were exposed to hepI under constant conditions of pressure (80 mmHg) and flow (no flow) in vitro. These experiments were deliberately performed in arteries of 12 week old SHR that display an inward eutrophic remodeling which contributes to the increased peripheral resistance and blood pressure [24, 29]. In the untreated arteries, the diameter at 80 mmHg and the relationship between passive diameter and transmural pressure did not change during the 3 day culture period (Fig. 4). The presence of 1 μmol/L hepI, however, resulted in an increase of the diameter at 80 mmHg and in an upward shift of the pressure-diameter curves (p < 0.05 for day 1, day 2 and day 3)(Fig. 4). Arterial structural diameter was increased by 7.5 ± 1.9 % within 24 hours and increased further to +12.6 ± 2.4 % after 3 days (Fig. 4). Exposure to hepI did not modify calculated distensibility (Fig. 4), general arterial histology (not shown), and did not result in statistically significant changes in media cross sectional area (13693 ± 4043 μm2 versus 12881 ± 3182 μm2) or cell number (52 ± 11 versus 54 ± 8 nuclear profiles/section) indicating that the hepI-induced outward remodeling was eutrophic in nature.

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