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Suppressed vascular Rho-kinase activation is a protective cardiovascular mechanism in obese female mice
Gabriela S Barbosa1,2,3, Rafael Menezes Costa1,2, Wanessa M C Awata1,2
1Department of Pediatrics, UPMC Children's Hospital of Pittsburgh at University of Pittsburgh, Pittsburgh, PA, U.S.A.
Background:
Obesity is the number one cardiovascular risk factor for both men and women and is a complex condition. Although a sex dimorphism on vascular function has already been noted, the underlying processes remain unclear. The Rho-kinase pathway has a unique role in controlling vascular tone, and in obese male mice, hyperactivation of this system results in worsened vascular constriction. We investigated whether female mice exhibit decreased Rho-kinase activation as a protective mechanism in obesity.
Methods:
We exposed male and female mice to a high-fat diet (HFD) for 14 weeks. At the end, energy expenditure, glucose tolerance, adipose tissue inflammation, and vascular function were investigated.
Results:
Male mice were more sensitive to HFD-induced body weight gain, glucose tolerance, and inflammation than female mice. After establishing obesity, female mice demonstrated increase in energy expenditure, characterized by an increase in heat, whereas male mice did not. Interestingly, obese female mice, but not male, displayed attenuated vascular contractility to different agonists, such difference was blunted by inhibition of Rho-kinase, which was accompanied by a suppressed Rho-kinase activation, measured by Western blot. Finally, aortae from obese male mice displayed an exacerbated inflammation, whereas obese female demonstrated a mild vascular inflammation.
Conclusion:
In obesity, female mice demonstrate a vascular protective mechanism-suppression of vascular Rho-kinase-to minimize the cardiovascular risk associated with obesity, whereas male mice do not generate any adaptive response. Future investigations can help to understand how Rho-kinase becomes suppressed in female during obesity.
Insights
Female mice exhibit a protective vascular mechanism against obesity by suppressing Rho-kinase activation, unlike male mice. This finding highlights sex differences in cardiovascular risk associated with obesity.
Area of Science:
- Cardiovascular physiology
- Endocrinology
- Obesity research
Background:
- Obesity is a primary cardiovascular risk factor with unclear sex-based differences in vascular effects.
- The Rho-kinase pathway regulates vascular tone, and its hyperactivation worsens constriction in obese males.
- Investigating Rho-kinase activation in female mice during obesity is crucial.
Purpose of the Study:
- To determine if female mice exhibit decreased Rho-kinase activation as a protective mechanism against obesity-related cardiovascular risks.
- To compare the effects of a high-fat diet on metabolic and vascular parameters between male and female mice.
Main Methods:
- Male and female mice were fed a high-fat diet (HFD) for 14 weeks.
- Evaluated energy expenditure, glucose tolerance, adipose tissue inflammation, and vascular function.
- Rho-kinase activation was measured via Western blot, and vascular contractility was assessed.
Main Results:
- Female mice showed less weight gain, improved glucose tolerance, and increased energy expenditure compared to males on HFD.
- Obese females displayed reduced vascular contractility and inflammation, linked to suppressed Rho-kinase activation.
- Obese males exhibited exacerbated vascular inflammation and heightened Rho-kinase activity.
Conclusions:
- Female mice possess an obesity-induced vascular protective mechanism involving Rho-kinase suppression, mitigating cardiovascular risk.
- Male mice lack comparable adaptive responses, suggesting distinct sex-specific pathophysiological pathways in obesity.
- Further research is needed to elucidate the mechanisms of Rho-kinase suppression in females during obesity.
