CORRESPONDENCE: RESEARCH CORRESPONDENCE
Gender Differences in Endothelial Tissue-Type Plasminogen Activator Release in Middle-Aged Adults
Brian L. Stauffer, MD*,
Greta L. Hoetzer, PhD,
Gary P. Van Guilder, MS,
Derek T. Smith, PhD and
Christopher A. DeSouza, PhD
* Integrative Vascular Biology Laboratory, University of Colorado, 354 UCB, Boulder, CO 80309 (Email: brian.stauffer{at}colorado.edu).
To the Editor:
Between the ages of 45 and 65 years, the incidence of myocardial infarction is three times higher in men compared with women. In addition, the prevalence of thrombotic stroke is  50% greater in men than women (1). The mechanisms behind this gender difference in atherothrombotic events remain unclear. Impaired endothelial regulation of fibrinolysis, specifically reduced capacity to release tissue-type plasminogen activator (t-PA), has been linked directly to increased atheromatous plaque burden and increased coronary atherothrombosis (2,3). Endothelial t-PA release is the predominant physiologic mechanism governing endogenous fibrinolysis. Currently, it is unknown if a gender difference in endothelial t-PA release exists. If so, this may contribute to the gender-related disparity in the prevalence and incidence of atherothrombotic events in middle-aged adults. We tested the hypothesis that the capacity of the endothelium to release t-PA is greater in middle-aged women compared with men.
Sixty-six healthy sedentary adult humans ages 45 to 65 years were studied: 30 men (58 ± 1 year) and 36 women (58 ± 1 year). All subjects were nonobese (body mass index  30 kg/m2), normotensive (blood pressure <140/90 mm Hg), nonsmokers, nonmedicated, and free of overt cardiovascular, metabolic, and hematologic disease, which were assessed by medical history, resting and exercise electrocardiograms, and fasting blood chemistries. The women were at least one year postmenopausal (range 1 to 32 years) and had never taken or had discontinued use of hormone replacement therapy at least one year before the start of the study. Before participation, the subjects provided written informed consent according to the guidelines of the University of Colorado at Boulder.
Endothelial release of t-PA antigen and plasminogen activator inhibitor (PAI)-1 antigen in response to bradykinin and sodium nitroprusside was determined using an isolated forearm model. Net release or uptake rates were calculated as follows: net release = (CV – CA) x (FBF x [101 – hematocrit/100]), where CV and CA represent the concentration in the vein and artery, respectively, and FBF represents forearm blood flow. The total amount of t-PA antigen released across the forearm in response to bradykinin was calculated as the area under each curve above baseline using a trapezoidal model. Bradykinin was infused intra-arterially at 12.5, 25, and 50 ng/100 ml tissue/min and sodium nitroprusside at 1, 2, and 4 µg/100 ml tissue/min for 5 min at each dose. To avoid an order effect, the sequence of drug administration was randomized. Plasma concentrations of t-PA and PAI-1 antigen were determined by enzyme immunoassay.
Differences in subject baseline characteristics and area under the curve data were determined by unpaired t test. Group differences in FBF and endothelial t-PA and PAI-1 release to bradykinin and sodium nitroprusside were determined by repeated measures analysis of variance. The relationships among the variables of interest were assessed by means of Pearson’s correlation coefficient and linear regression analysis. Data are reported as mean ± SEM. Statistical significance was set at p < 0.05.
Although none of the subjects was obese, the men demonstrated higher (all p < 0.05) body mass (81.8 ± 1.5 kg vs. 65.4 ± 1.6 kg), body mass index (26.1 ± 0.5 kg/m2 vs. 24.4 ± 0.6 kg/m2), and waist circumference (94.1 ± 1.7 cm vs. 83.2 ± 2.1 cm), whereas the women had a higher percentage of body fat (35.7 ± 1.1% vs. 25.8 ± 0.5%). The FBF responses to bradykinin and sodium nitroprusside were modestly (15%) but significantly higher in the men.
Basal net release of t-PA antigen was not significantly different between the groups. In response to bradykinin, net release of t-PA antigen increased in a dose-dependent fashion in both groups; however, the response was significantly greater in the women (from 0.9 ± 0.6 ng/100 ml tissue/min to 72.6 ± 5.3 ng/100 ml tissue/min) compared with the men (0.9 ± 0.6 ng/100 ml tissue/min to 45.7 ± 3.3 ng/100 ml tissue/min). As a result, the total amount of t-PA antigen released (area under the curve) was 46% higher (p < 0.01) in the women than the men (344 ± 27 ng/100 ml tissue vs. 235 ± 20 ng/100 ml of tissue) (Fig. 1). Sodium nitroprusside elicited no significant changes in endothelial t-PA antigen release in either group. The effects of bradykinin and sodium nitroprusside on the net release of PAI-1 antigen were minimal and not significantly different between groups. No significant correlation was found between any anthropometric or metabolic variable and t-PA release in either group.
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Figure 1 Net release rate and total amount of tissue-type plasminogen activator (t-PA) antigen released (area under the curve) across the forearm in response to bradykinin in men and women. Values are mean ± SEM. *p < 0.05 vs. men.
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The primary new finding of the present investigation is that endothelial release of t-PA occurs in a gender-specific fashion in healthy middle-aged adults. Indeed, the rate and total amount of t-PA released from the endothelium were 50% higher in middle-aged women compared with men. Our findings demonstrate a major gender-related difference in an important endogenous defense mechanism against thrombosis.
The reasons for the overwhelming gender disparity in cardiovascular disease rates in middle-aged adults are unclear. Scrutiny of epidemiologic data indicates no significant gender-related differences in the incidence and prevalence of traditional cardiovascular disease risk factors in middle-aged adults (1). To the best of our knowledge, this study is the first to demonstrate gender-specific differences in the capacity of the endothelium to release t-PA in middle-aged adults. Endothelial release of t-PA is the crucial step in the prevention of clot propagation and plays a central role in maintaining vascular patency. Importantly, diminished t-PA release is associated with atherosclerotic disease and clinical cardiovascular events (2–5). Given the lack of appreciable gender discrepancy in other important risk factors, the observed difference in endothelial t-PA release may be a function of intrinsic genetic phenotypes between men and women. Indeed, there is evidence linking specific genetic expression profiles with gender differences in arterial stiffness (6). We are currently exploring potential gender-related differences in polymorphisms associated with t-PA release.
Although the men demonstrated greater vasodilator capacity than the women, we do not believe that the difference (15%) is physiologically or clinically remarkable. What the FBF responses clearly indicate is that the noted gender difference in t-PA release was not a blood flow-related phenomenon. Despite higher FBF responses to bradykinin, the men exhibited lower endothelial release of t-PA than women. More importantly, when viewed collectively the divergent vasomotor and fibrinolytic responses highlight the complexities of gender-related differences in vascular function that, in turn, impact disease development.
In conclusion, the results of the present study identify a marked difference in the capacity of the endothelium to acutely release t-PA between middle-aged men and women. Endothelial fibrinolytic function may be an important physiologic mechanism underlying the profound gender-related difference in the incidence and prevalence of atherothrombotic events in middle-aged adults.
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Footnotes
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Please note: this work was supported by grants NIH HL06830, DK62061, and 2 MO1-RR00051.
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References
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- American Heart Association Heart Disease and Stroke Statistics—2004 update. Dallas, TX: American Heart Association; 2003.
- Newby DE, Wright RA, Labinjoh C, et al. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smokinga mechanism for arterial thrombosis and myocardial infarction. Circulation 1999;99:1411-1415.[Abstract/Free Full Text]
- Newby DE, McLeod AL, Uren NG, et al. Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smokingdirect link between endothelial dysfunction and atherothrombosis. Circulation 2001;103:1936-1941.[Abstract/Free Full Text]
- Carmeliet P, Schoonjans L, Kieckens L, et al. Physiological consequences of loss of plasminogen activator gene function in mice Nature 1994;368:419-424.[CrossRef][Medline]
- Christie PD, Edelberg JM, Picard MH, et al. A murine model of myocardial microvascular thrombosis J Clin Invest 1999;104:533-539.[ISI][Medline]
- Durier S, Fassot C, Laurent S, et al. Physiological genomics of human arteriesquantitative relationship between gene expression and arterial stiffness. Circulation 2003;108:1845-1851.[Abstract/Free Full Text]
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