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Gender-specific modulation of the response to arterial injury by soluble guanylate cyclase α1.

Vermeersch P, Buys E, Sips P, Pokreisz P, Marsboom G, Gillijns H, Pellens M, Dewerchin M, Bloch KD, Brouckaert P, Janssens S - Open Cardiovasc Med J (2009)

Bottom Line: NO modulates vascular tone and structure but the relative contributions of cGMP-dependent versus cGMP-independent mechanisms remain uncertain.In contrast, sGCα1, sGCα2, and sGCβ1 mRNA expression did not differ between groups. ³H-thymidine incorporation in cultured sGCa1(-/-) smooth muscle cells (SMC) was 27%±12% lower than in WT SMC and BrdU-incorporation in carotid arteries 5 days after ligation was significantly less in sGCa1(-/-) M than in WT M.Functional deletion of sGCa1 resulted in reduced cGMP levels in male sGCa1(-/-) mice and a gender-specific effect on the adaptive response to vascular injury.

View Article: PubMed Central - PubMed

Affiliation: Vesalius Research Center (VIB) and Cardiac Unit.

ABSTRACT

Objective: Soluble guanylate cyclase (sGC), a heterodimer composed of alpha and beta subunits, synthesizes cGMP in response to nitric oxide (NO). NO modulates vascular tone and structure but the relative contributions of cGMP-dependent versus cGMP-independent mechanisms remain uncertain. We studied the response to vascular injury in male (M) and female (F) mice with targeted deletion of exon 6 of the sGCα1 subunit (sGCα1(-/-)), resulting in a non-functional heterodimer.

Methods: We measured aortic cGMP levels and mRNA transcripts encoding sGC α1, α2, and β1 subunits in wild type (WT) and sGCa1(-/-) mice. To study the response to vascular injury, BrdU-incorporation and neointima formation (maximum intima to media (I/M) ratio) were determined 5 and 28 days after carotid artery ligation, respectively.

Results: Aortic cGMP levels were 4-fold higher in F than in M mice in both genotypes, and, within each gender, 4-fold higher in WT than in sGCa1(-/-). In contrast, sGCα1, sGCα2, and sGCβ1 mRNA expression did not differ between groups. ³H-thymidine incorporation in cultured sGCa1(-/-) smooth muscle cells (SMC) was 27%±12% lower than in WT SMC and BrdU-incorporation in carotid arteries 5 days after ligation was significantly less in sGCa1(-/-) M than in WT M. Neointima area and I/M 28 days after ligation were 65% and 62% lower in sGCa1(-/-) M than in WT M mice (p<0,05 for both) but were not different in F mice.

Conclusion: Functional deletion of sGCa1 resulted in reduced cGMP levels in male sGCa1(-/-) mice and a gender-specific effect on the adaptive response to vascular injury.

No MeSH data available.


Related in: MedlinePlus

The average maximum I/M ratio in WT male mice (panel A) was significantly higher than in sGCα1-/- male mice (panel B). The neointima (NI) was almost exclusively composed of SMC actin positive cells (panel C), while almost no CD45-positive cells (panel D) could be detected in the neointima or the media (M) between the internal and external elastic laminae (arrowheads, panel D). CD45 immunoreactivity was predominantly observed in the adventitia (A).
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Figure 3: The average maximum I/M ratio in WT male mice (panel A) was significantly higher than in sGCα1-/- male mice (panel B). The neointima (NI) was almost exclusively composed of SMC actin positive cells (panel C), while almost no CD45-positive cells (panel D) could be detected in the neointima or the media (M) between the internal and external elastic laminae (arrowheads, panel D). CD45 immunoreactivity was predominantly observed in the adventitia (A).

Mentions: To evaluate the role of sGC gene function in the adaptive response to vascular injury, the common carotid artery was surgically ligated in WT and sGCα1-/- mice. The maximum I/M ratio in both genotypes was observed at a distance ranging from +50 to +500 μm proximal to the ligation, while almost no neointima was observed beyond +1000 μm. Maximum I/M ratio 28 days after ligation was lower in sGCα1-/- M than in WT M mice (p<0.05, Figs. 3A and 3B, respectively) but was not different in F mice (Fig. 4A). Neointima area was also lower in sGCα1-/- M compared to WT M or F mice of either genotype (p<0.05 vs. all). Media area and IEL length did not differ between groups (Table 2). The neointimal cells 4 weeks after ligation showed marked SMC actin immunoreactivity (Fig. 3C), while almost no CD45-positive inflammatory cells were observed in the neointima or the media (Fig. 3D). CD45 immunoreactivity was predominantly observed in the adventitia.


Gender-specific modulation of the response to arterial injury by soluble guanylate cyclase α1.

Vermeersch P, Buys E, Sips P, Pokreisz P, Marsboom G, Gillijns H, Pellens M, Dewerchin M, Bloch KD, Brouckaert P, Janssens S - Open Cardiovasc Med J (2009)

The average maximum I/M ratio in WT male mice (panel A) was significantly higher than in sGCα1-/- male mice (panel B). The neointima (NI) was almost exclusively composed of SMC actin positive cells (panel C), while almost no CD45-positive cells (panel D) could be detected in the neointima or the media (M) between the internal and external elastic laminae (arrowheads, panel D). CD45 immunoreactivity was predominantly observed in the adventitia (A).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2743853&req=5

Figure 3: The average maximum I/M ratio in WT male mice (panel A) was significantly higher than in sGCα1-/- male mice (panel B). The neointima (NI) was almost exclusively composed of SMC actin positive cells (panel C), while almost no CD45-positive cells (panel D) could be detected in the neointima or the media (M) between the internal and external elastic laminae (arrowheads, panel D). CD45 immunoreactivity was predominantly observed in the adventitia (A).
Mentions: To evaluate the role of sGC gene function in the adaptive response to vascular injury, the common carotid artery was surgically ligated in WT and sGCα1-/- mice. The maximum I/M ratio in both genotypes was observed at a distance ranging from +50 to +500 μm proximal to the ligation, while almost no neointima was observed beyond +1000 μm. Maximum I/M ratio 28 days after ligation was lower in sGCα1-/- M than in WT M mice (p<0.05, Figs. 3A and 3B, respectively) but was not different in F mice (Fig. 4A). Neointima area was also lower in sGCα1-/- M compared to WT M or F mice of either genotype (p<0.05 vs. all). Media area and IEL length did not differ between groups (Table 2). The neointimal cells 4 weeks after ligation showed marked SMC actin immunoreactivity (Fig. 3C), while almost no CD45-positive inflammatory cells were observed in the neointima or the media (Fig. 3D). CD45 immunoreactivity was predominantly observed in the adventitia.

Bottom Line: NO modulates vascular tone and structure but the relative contributions of cGMP-dependent versus cGMP-independent mechanisms remain uncertain.In contrast, sGCα1, sGCα2, and sGCβ1 mRNA expression did not differ between groups. ³H-thymidine incorporation in cultured sGCa1(-/-) smooth muscle cells (SMC) was 27%±12% lower than in WT SMC and BrdU-incorporation in carotid arteries 5 days after ligation was significantly less in sGCa1(-/-) M than in WT M.Functional deletion of sGCa1 resulted in reduced cGMP levels in male sGCa1(-/-) mice and a gender-specific effect on the adaptive response to vascular injury.

View Article: PubMed Central - PubMed

Affiliation: Vesalius Research Center (VIB) and Cardiac Unit.

ABSTRACT

Objective: Soluble guanylate cyclase (sGC), a heterodimer composed of alpha and beta subunits, synthesizes cGMP in response to nitric oxide (NO). NO modulates vascular tone and structure but the relative contributions of cGMP-dependent versus cGMP-independent mechanisms remain uncertain. We studied the response to vascular injury in male (M) and female (F) mice with targeted deletion of exon 6 of the sGCα1 subunit (sGCα1(-/-)), resulting in a non-functional heterodimer.

Methods: We measured aortic cGMP levels and mRNA transcripts encoding sGC α1, α2, and β1 subunits in wild type (WT) and sGCa1(-/-) mice. To study the response to vascular injury, BrdU-incorporation and neointima formation (maximum intima to media (I/M) ratio) were determined 5 and 28 days after carotid artery ligation, respectively.

Results: Aortic cGMP levels were 4-fold higher in F than in M mice in both genotypes, and, within each gender, 4-fold higher in WT than in sGCa1(-/-). In contrast, sGCα1, sGCα2, and sGCβ1 mRNA expression did not differ between groups. ³H-thymidine incorporation in cultured sGCa1(-/-) smooth muscle cells (SMC) was 27%±12% lower than in WT SMC and BrdU-incorporation in carotid arteries 5 days after ligation was significantly less in sGCa1(-/-) M than in WT M. Neointima area and I/M 28 days after ligation were 65% and 62% lower in sGCa1(-/-) M than in WT M mice (p<0,05 for both) but were not different in F mice.

Conclusion: Functional deletion of sGCa1 resulted in reduced cGMP levels in male sGCa1(-/-) mice and a gender-specific effect on the adaptive response to vascular injury.

No MeSH data available.


Related in: MedlinePlus