Greater TIMP-1 protein levels and neointimal formation represent sex-dependent cellular events limiting aortic vessel expansion in female rats

Fragmentation/loss of the structural protein elastin represents the precipitating event translating to aortic expansion and subsequent aneurysm formation. The present study tested the hypothesis that greater protein expression of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and neointimal growth secondary to a reduction of medial elastin content represent sex-dependent events limiting aortic vessel expansion in females. TIMP-1 protein levels were higher in the ascending aorta of female versus male patients diagnosed with a bicuspid aortic valve (BAV). The latter paradigm was recapitulated in the aorta of adult male and female rats complemented by greater TIMP-2 expression in females. CaCl₂ (0.5 M) treatment of the infrarenal aorta of adult male and female rats increased the in situ vessel diameter and expansion was significantly smaller in females despite a comparable reduction of medial elastin content. The preferential appearance of a neointimal region of the CaCl₂-treated infrarenal aorta of female rats may explain in part the smaller in situ expansion and neointimal growth correlated positively with the % change of the in situ diameter. Neointimal formation was secondary to a significant increase in the density of medial/neointimal vascular smooth muscle cells (VSMCs) that re-entered the G₂-M phase whereas VSMC cell cycle re-entry was attenuated in the CaCl₂-treated infrarenal aorta of male rats. Thus, greater TIMP-1 expression in the aorta of female BAV patients may prevent excessive elastin fragmentation and preferential neointimal growth following CaCl₂-treatment of the infrarenal aorta of female rats represents a sex-dependent biological event limiting vessel expansion secondary to a significant loss of the structural protein.