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

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.