Early manifestation of aging-related vascular dysfunction in human penile vasculature-A potential explanation for the role of erectile dysfunction as a harbinger of systemic vascular disease

Abstract

Advanced age is related to functional alterations of human vasculature, but erectile dysfunction precedes systemic manifestations of vascular disease. The current study aimed to simultaneously evaluate the influence of aging on vascular function (relaxation and contraction responses) in systemic human vascular territories: aorta (HA) and resistance mesenteric arteries (HMA) and human corpus cavernosum (HCC) and penile resistance arteries (HPRA). Associations of oxidative stress and inflammation circulating biomarkers with age and functional responses were also determined. Vascular specimens were obtained from 76 organ donors (age range 18-87). Four age-groups were established: < 40, 40-55, 56-65 and > 65 years old. Increasing age was associated with a decline in endothelium-dependent relaxation induced by BK in HMA (r = -0.597, p = 0.0001), or by ACh in HCC (r = -0.505, p = 0.0022), and HPRA (r = -0.601, p = 0.0012). Significant impairment was detected at > 65 years old in HMA but earlier in penile vasculature (> 55 years old). Age-related reduction to H₂O₂-vasodilatory response started before in HCC (56-65 years old) than in HA (> 65 years old). In contrast to relaxation responses, aging-related hypercontractility to adrenergic stimulation was homogeneous: contractions significantly increased in subjects > 55 years old in all tested vessels. Although not significantly age related, circulating levels of ADMA (r = -0.681, p = 0.0052) and TNF-α (r = -0.537, p = 0.0385) were negatively correlated with endothelial vasodilation in HMA but not in HCC or HPRA. Penile vasculature exhibits an early impairment of endothelium-dependent and H₂O₂-induced vasodilations when compared to mesenteric microcirculation and aorta. Therefore, functional susceptibility of penile vasculature to the aging process may account for anticipation of erectile dysfunction to systemic manifestations of vascular disease.

Keywords: Aorta; Biomarkers; Corpus cavernosum; Endothelial vasodilation; Erectile dysfunction; Human; Microvasculature; Vascular aging.

Fig. 1

Aging differentially impacts endothelium-dependent vasodilation in human mesenteric arteries (HMA), corpus cavernosum (HCC) and penile resistance arteries (HPRA). Panels A to C show associations between age and endothelium-dependent vasodilation determined as –log molar of concentration required to obtain 50% relaxation (pEC₅₀) for bradykinin (BK) in isolated HMA (A), for acetylcholine (ACh) in isolated HCC (B) and HPRA (C) from donors aged between 20 and 87 years. Every point represents the averaged pEC₅₀ values of segments/strips from one single subject. Coefficients of determination and p for associations are indicated. Complete concentration–response curves of endothelium-dependent relaxation to BK in HMA (D) precontracted with U46619 and in HCC (E) precontracted with phenylephrine (PE) and in HPRA (F) precontracted with norepinephrine (NE) obtained from < 40, 40–55, 56–65 and > 65-year-old groups are shown. Data are expressed as mean ± SEM of the percentage of maximal relaxation induced by papaverine (0.1 mM) at the end of the experiment. n indicates the number of subjects. * p < 0.05, *** p < 0.001 vs. data obtained in < 40-year-old group by a two-factors ANOVA test followed by Bonferroni’s correction. pEC₅₀ values for BK in HMA (G) and for ACh in HCC (H) and HPRA (I) were averaged and plotted against average age for each age group. † p < 0.05, ††† p < 0.001 vs. data obtained in < 40-year-old group by a one-factor ANOVA test followed by Dunnet’s test for multiple comparisons. The percentage of the precontraction elicited by U44619 in HMA, by PE in HPRA and by NE in HCC with respect to K⁺ were: HMA: < 40 years: 108.1 ± 11.7%; 40–55 years: 97.0 ± 6.1%, 56–65 years: 116.6 ± 9.1%, and > 65 years: 122.7 ± 11.6%; HCC: < 40 years: 63.8 ± 10.4%; 40–55 years: 65.7 ± 8.4%, 56–65 years: 64.0 ± 11.2%, and > 65 years: 66.9 ± 13.9% and HPRA: < 40 years: 80.9 ± 9.1%; 40–55 years: 74.8 ± 5.9, 56–65 years: 72.9 ± 5.4%, and > 65 years: 88.4 ± 5.8%, p > 0.05 for all comparisons among age groups by one-factor ANOVA followed by Dunnet’s test

Fig. 2

Effects of aging on hydrogen peroxide (H₂O₂)-induced vasodilation in human aortic strips (HA) and corpus cavernosum (HCC). Upper panels show association between age and H₂O₂-induced vasodilation determined as maximum response (E_max) to H₂O₂ in HA (A) and HCC (B) from donors. Every point represents the averaged E_max values of strips from one single subject. Lower panels show complete concentration–response curves of H₂O₂–induced relaxation in HA (C) precontracted with norepinephrine (NE) and in HCC (D) precontracted with phenylephrine (PE) obtained from < 40, 40–55, 56–65 and > 65-year-old groups. Data are expressed as mean ± SEM of the percentage of maximal relaxation induced by papaverine (0.1 mM) at the end of the experiment. n indicates the number of subjects. *** p < 0.001 vs. data obtained in < 40-year-old group by a two-factors ANOVA test followed by Bonferroni’s correction. The percentage of the precontraction with respect to K⁺ in the different vascular territories evaluated were: HA: < 40 years: 81.9 ± 12.5%, 40–55 years: 91.7 ± 11.7%, 56–65 years: 88.5 ± 13.0%, and > 65 years: 95.2 ± 14.6%, and HCC: < 40 years: 66.9 ± 11.7%, 40–55 years: 65.0 ± 8.3%, 56–65 years: 69.2 ± 8.0%, and > 65 years: 65.2% ± 10.3%; p > 0.05 for all comparisons among age groups by one-factor ANOVA followed by Dunnet’s test.

Fig. 3

Aging is associated with adrenergic hypercontractility in human mesenteric arteries (HMA), aortic strips (HA), corpus cavernosum (HCC), and penile resistance arteries (HPRA). Left panels show associations between age and adrenergic contraction in HMA (A), HA (C), HCC (E), and HPRA (G) determined as the maximum response (E_max) to norepinephrine (NE) expressed as the percentage of K⁺-induced contraction. Every point represents the averaged E_max values of segments/strips from one single subject. Right panels show complete concentration–response curves of NE–induced contraction in HMA (B), HA (D), HCC (F), and HPRA (H) obtained from < 40, 40–55, 56–65 and > 65-year-old groups. Data are expressed as mean ± SEM of the percentage of K⁺-induced contraction. n indicates the number of subjects. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. data obtained in < 40-year-old group by a two-factor ANOVA test followed by Bonferroni’s correction

Fig. 4

Associations of circulating biomarkers with endothelium-dependent vasodilation in human mesenteric arteries (HMA) and human corpus cavernosum (HCC). Linear regressions of values of pEC₅₀ for bradykinin (BK) obtained in HMA (A, C) and values of pEC₅₀ for acetylcholine (ACh) obtained in HCC (B, D) with respect to circulating levels of asymmetric dimethyl arginine (ADMA) (A, B) and tumour necrosis factor-α (TNF-α) (C, D) obtained in the same donors. Coefficients of determination (r²) and p values are indicated for each association. Significant correlations are highlighted in bold plus italic text