Sex/Gender Medicine  The Biological Basis for Personalized Care in Cardiovascular Medicine

Arain, Faisal A.; Kuniyoshi, Fatima H. Sert; Abdalrhim, Ahmed D.; Miller, Virginia M.

doi:10.1253/circj.cj-09-0588

Cited by 76 publications

(17 citation statements)

References 131 publications

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“…These gender differences suggest that loss of NO is likely to have a greater impact on the regulation of cochlear blood flow in males than in females, which is consistent with animal experiments and clinical outcomes that suggest a gender preference in hearing loss, with males being more susceptible [41], [42]. Given the higher propensity of cardiovascular disease in males compared to females [43], our results point to possible mechanisms that may underlie the greater susceptibility of males to age-related hearing loss. Given the promise of rho-kinase inhibitors in treating cardiovascular disorders, the results from this study provide a basis for exploring the use of rho-kinase inhibitors in the treatment of hearing loss in males [44], [45].…”

Section: Discussionsupporting

confidence: 68%

NOS Inhibition Enhances Myogenic Tone by Increasing Rho-Kinase Mediated Ca2+ Sensitivity in the Male but Not the Female Gerbil Spiral Modiolar Artery

2013

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Cochlear blood flow regulation is important to prevent hearing loss caused by ischemia and oxidative stress. Cochlear blood supply is provided by the spiral modiolar artery (SMA). The myogenic tone of the SMA is enhanced by the nitric oxide synthase (NOS) blocker L-NG-Nitro-Arginine (LNNA) in males, but not in females. Here, we investigated whether this gender difference is based on differences in the cytosolic Ca2+ concentration and/or the Ca2+ sensitivity of the myofilaments. Vascular diameter, myogenic tone, cytosolic Ca2+, and Ca2+ sensitivity were evaluated in pressurized SMA segments isolated from male and female gerbils using laser-scanning microscopy and microfluorometry. The gender difference of the LNNA-induced tone was compared, in the same vessel segments, to tone induced by 150 mM K+ and endothelin-1, neither of which showed an apparent gender-difference. Interestingly, LNNA-induced tone in male SMAs was observed in protocols that included changes in intramural pressure, but not when the intramural pressure was held constant. LNNA in male SMAs did not increase the global Ca2+ concentration in smooth muscle cells but increased the Ca2+ sensitivity. This increase in the Ca2+ sensitivity was abolished in the presence of the guanylyl cyclase inhibitor ODQ or by extrinsic application of either the nitric oxide (NO)-donor DEA-NONOate or the cGMP analog 8-pCPT-cGMP. The rho-kinase blocker Y27632 decreased the basal Ca2+ sensitivity and abolished the LNNA-induced increase in Ca2+ sensitivity in male SMAs. Neither LNNA nor Y27632 changed the Ca2+ sensitivity in female SMAs. The data suggest that the gender difference in LNNA-induced tone is based on a gender difference in the regulation of rho-kinase mediated Ca2+ sensitivity. Rho-kinase and NO thus emerge as critical factors in the regulation of cochlear blood flow. The larger role of NO-dependent mechanisms in male SMAs predicts greater restrictions on cochlear blood flow under conditions of impaired endothelial cell function.

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Section: Discussionsupporting

confidence: 68%

NOS Inhibition Enhances Myogenic Tone by Increasing Rho-Kinase Mediated Ca2+ Sensitivity in the Male but Not the Female Gerbil Spiral Modiolar Artery

2013

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“…Nonetheless, perspectives, editorials and reviews in several journals all highlight the idea that sex steroids “do more” than play a role in reproductive function. Certainly, this has been most established in the cardiovascular (Arain et al, 2009; Konhilas, 2010; Leuzzi et al, 2010; Miller, 2010; Perez-Lopez et al, 2010), metabolism (Beierle et al, 1999; Bigos et al, 2009; Greenhill, 2011; Wang et al, 2011), and cognition (Gillies & McArthur; Hines, 2010; Janicki & Schupf, 2010; Manson, 2008; McEwen, 2010; McEwen & Alves, 1999; Reddy, 2010) arenas, but there are now increasing reports of sex steroid effects in different lung components, and how they may play a role in important diseases such as asthma, Chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, cancer and even pulmonary hypertension. Accordingly, the major goal of this review is to highlight this research relating to sex steroids and their effects on lung components in health and disease.…”

Section: Introductionmentioning

confidence: 99%

Sex steroid signaling: Implications for lung diseases

Sathish

Martin

Prakash

2015

Pharmacology & Therapeutics

144

134

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There is increasing recognition that the sex hormones (estrogen, progesterone, and testosterone) have biological and pathophysiological actions in peripheral, non-reproductive organs, including the lung. Clinically, sex differences in the incidence, morbidity and mortality of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, lung cancer and pulmonary hypertension have been noted, although intrinsic sex differences vs. the roles of sex steroids are still not well-understood. Accordingly, it becomes important to ask the following questions: 1) Which sex steroids are involved? 2) How do they affect different components of the lung under normal circumstances? 3) How does sex steroid signaling change in or contribute to lung disease, and in this regard, are sex steroids detrimental or beneficial? As our understanding of sex steroid signaling in the lung improves, it is important to consider whether such information can be used to develop new therapeutic strategies to target lung diseases, perhaps in both sexes or in a sex-specific manner. In this review, we focus on the basics of sex steroid signaling, and the current state of knowledge regarding how they influence structure and function of specific lung components across the life span and in the context of some important lung diseases. We then summarize the potential for sex steroids as useful biomarkers and therapeutic targets in these lung diseases as a basis for future translational research in the area of gender and individualized medicine.

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“…Our understanding of sex-specific cardiovascular control mechanisms is limited due to a predominance of male-only human and animal studies (Huxley 2007; Arain et al 2009; Miller 2010, 2014), as well as, a lack of mechanistic studies directly comparing men and women. Within this context, exercise elicits a robust local vasodilation, offering an excellent model to examine dynamic vascular control mechanisms between the sexes.…”

Section: Introductionmentioning

confidence: 99%

Exercise vasodilation is greater in women: contributions of nitric oxide synthase and cyclooxygenase

et al. 2015

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Purpose We hypothesized exercise vasodilation would be greater in women due to nitric oxide synthase (NOS) and cyclooxygenase (COX) signaling. Methods 45 healthy adults (23 women, W, 22 men, M, 26 ± 1 years) completed two 10-min trials of dynamic forearm exercise at 15 % intensity. Forearm blood flow (FBF; Doppler ultrasound), arterial pressure (brachial catheter), and forearm lean mass were measured to calculate relative forearm vascular conductance (FVCrel) = F BF 100 mmHg−1 100 g−1 lean mass. Local intra-arterial infusion of L-NMMA or ketorolac acutely inhibited NOS and COX, respectively. In Trial 1, the first 5 min served as control exercise (CON), followed by 5 min of L-NMMA or ketorolac over the last 5 min of exercise. In Trial 2, the remaining drug was infused during 5–10 min, to achieve combined NOS–COX inhibition (double blockade, DB). Results Are mean ± SE. Women exhibited 29 % greater vasodilation in CON (AFVCrel, 19 ± 1 vs. 15 ± 1, p = 0.01). L-NMMA reduced AFVCrel (p < 0.001) (W: Δ −2.3 ± 1.3 vs. M: Δ −3.7 ± 0.8, p = 0.25); whereas, ketorolac modestly increased ΔFVCrel (p = 0.04) similarly between sexes (W: Δ 1.6 ± 1.1 vs. M: Δ 2.0 ± 1.6, p = 0.78). DB was also found to be similar between the sexes (p = 0.85). Conclusion These data clearly indicate women produce a greater exercise vasodilator response. Furthermore, contrary to experiments in animal models, these data are the first to demonstrate vascular control by NOS and COX is similar between sexes.

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Sex/Gender Medicine The Biological Basis for Personalized Care in Cardiovascular Medicine

Cited by 76 publications

References 131 publications

NOS Inhibition Enhances Myogenic Tone by Increasing Rho-Kinase Mediated Ca2+ Sensitivity in the Male but Not the Female Gerbil Spiral Modiolar Artery

NOS Inhibition Enhances Myogenic Tone by Increasing Rho-Kinase Mediated Ca2+ Sensitivity in the Male but Not the Female Gerbil Spiral Modiolar Artery

Sex steroid signaling: Implications for lung diseases

Exercise vasodilation is greater in women: contributions of nitric oxide synthase and cyclooxygenase

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