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. 2015 Mar;5(1):184-97.
doi: 10.1086/679724.

The sexual dimorphism associated with pulmonary hypertension corresponds to a fibrotic phenotype

Olga Rafikova  1 , Ruslan Rafikov  1 , Mary Louise Meadows  2 , Archana Kangath  2 , Danny Jonigk  3 , Stephen M Black  2
Affiliations

The sexual dimorphism associated with pulmonary hypertension corresponds to a fibrotic phenotype

Olga Rafikova et al. Pulm Circ. 2015 Mar.

Abstract

Although female predominance in the development of all types of pulmonary hypertension (PH) is well established, many clinical studies have confirmed that females have better prognosis and higher survival rate than males. There is no clear explanation of why sex influences the pathogenesis and progression of PH. Using a rat angioproliferative model of PH, which closely resembles the primary pathological changes observed in humans, we evaluated the role of sex in the development and progression of PH. Female rats had a more pronounced increase in medial thickness in the small pulmonary arteries. However, the infiltration of small pulmonary arteries by inflammatory cells was found only in male rats, and this corresponded to increased myeloperoxidase activity and abundant adventitial and medial fibrosis that were not present in female rats. Although the level of right ventricle (RV) peak systolic pressure was similar in both groups, the survival rate in male rats was significantly lower. Moreover, male rats presented with a more pronounced increase in RV thickness that correlated with diffuse RV fibrosis and significantly impaired right cardiac function. The reduction in fibrosis in female rats correlated with increased expression of caveolin-1 and reduced endothelial nitric oxide synthase-derived superoxide. We conclude that, in the pathogenesis of PH, female sex is associated with greater remodeling of the pulmonary arteries but greater survival. Conversely, in males, the development of pulmonary and cardiac fibrosis leads to early and severe RV failure, and this may be an important reason for the lower survival rate among males.

Keywords: caveolin-1; nitric oxide synthase; oxidative stress; superoxide.

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Figures

Figure 1
Figure 1
Sex-dependent differences in the survival rate of rats with pulmonary hypertension (PH). The survival curve of male and female rats during the 14-week study is shown. No deaths occurred in control groups (Cont) during this period of time. The survival rate in male but not female rats with PH was significantly different from that in controls. The survival rate in males with PH was also significantly different from that in female rats with PH. N = 6–10 rats in each group. Asterisk indicates P < 0.05 versus controls; dagger indicates P < 0.05 versus female rats with PH (log-rank test for trends).
Figure 2
Figure 2
Systemic and pulmonary pressure in male and female rats with pulmonary hypertension (PH). The systemic pressure was evaluated by measuring the mean arterial pressure (MAP) in the right carotid artery. No significant differences were found between groups (A). Echocardiography identified a significant decrease in pulmonary artery acceleration time (PAAT) in both male and female rats with PH starting at week 4 of the study (B). The RV peak systolic pressure (RVPSP) was also significantly increased in both male and female rats at week 14 of the study (C). Results are expressed as mean ± SEM; N = 5–8 rats in each group. Asterisk indicates P < 0.05 versus control group (Cont).
Figure 3
Figure 3
Female rats with pulmonary hypertension (PH) present with more severe angioproliferative changes in the lung. Representative images from hematoxylin-and-eosin-stained pulmonary arteries of control (Cont) male (A), control female (B), PH male (C), and PH female rats (D) are shown. Quantitative analysis of the vascular wall thickness (%VT) was significantly higher in both categories of pulmonary arteries examined (30–100 μm and 101–200 μm) in female rats with PH (E). Ten pulmonary arteries per each animal were analyzed. Results are expressed as mean ± SEM; N = 4 rats in each group. Asterisk indicates P < 0.05 versus Cont group. Dagger indicates P < 0.05 versus male PH group. The black bar corresponds to 100 μm.
Figure 4
Figure 4
The inflammatory response is more pronounced in male rats with pulmonary hypertension (PH). Perivascular infiltration by inflammatory cells was primarily found in male (A; arrows) but not female (B) rats with PH. Immunohistochemical analysis of the lungs using a myeloperoxidase (MPO) antibody (brown) revealed significant accumulation of MPO staining in the perivascular area in male (E; arrows) but not female rats with PH (F). Neither male (C) nor female control (Cont) rats (D) exhibited significant MPO staining. A significant increase in MPO activity, measured in peripheral lung tissue, was also found in male rats with PH (G). Results are expressed as mean ± SEM; N = 5–8 rats in each group. Asterisk indicates P < 0.05 versus Cont group; dagger indicates P < 0.05 versus male rats that were injected with a single dose of the vascular endothelial growth factor receptor 2 antagonist, SU5416. The black bar corresponds to 100 μm.
Figure 5
Figure 5
Male rats with pulmonary hypertension (PH) present with fibrotic changes in the adventitia and media of pulmonary arteries. Remodeling of the pulmonary arterial wall consisted of striking fibroproliferative changes in male rats with PH (A; arrows) and predominantly medial hypertrophy, without evidences of fibrosis, in female rats with PH (B). Masson trichrome staining identified low levels of extracellular matrix proteins in the adventitia of pulmonary arteries in control (Cont) male (C) and Cont female rats (D) as well as female rats with PH (F). However, abundant collagen accumulation was observed in the adventitia and media of pulmonary arteries from male rats with PH (E). Ten random fields (100×) for each animal were scored by a blinded observer. Scoring identified significant fibrotic tissue accumulation in male rats with PH and only mild fibrosis in female rats with PH (G). Results are expressed as mean ± SEM; N = 6 rats in each group. Asterisk indicates P < 0.05 versus Cont group. Dagger indicates P < 0.05 versus male rats that were injected with a single dose of the vascular endothelial growth factor receptor 2 antagonist, SU5416. The black bar corresponds to 100 μm.
Figure 6
Figure 6
Right ventricle (RV) hypertrophy and function. The thickness of the RV free wall was measured by echocardiography. In male rats with pulmonary hypertension (PH), there was a time-dependent increase in RV thickness (A), whereas female rats had only a mild increase in RV hypertrophy during exposure to hypoxia (first 4 weeks) with no subsequent increase in RV thickness (A). The wet weight ratio of RV wall normalized on left ventricle plus septum (LV+S)—Fulton index—was measured at 14 weeks. The Fulton index was significantly higher in male rats with PH (B). Attenuation in the RV peak diastolic pressure (RVPDP) was also observed only in male rats with PH (C). RV contractility and relaxation were evaluated by measuring RV dP/dtmax and dP/dtmin, respectively. RV contractility was significantly increased in both male and female rats with PH (D). However, the increase in RV relaxation was significantly impaired only in male rats (E). Results are expressed as mean ± SEM; N = 5–8 rats in each group. Asterisk indicates P < 0.05 versus control (Cont) group. Dagger indicates P < 0.05 versus male rats that were injected with a single dose of the VEGF receptor 2 antagonist, SU5416.
Figure 7
Figure 7
Severe myocardial fibrosis in the right ventricle (RV) of male rats with pulmonary hypertension (PH). Myocardial tissues, subjected to Masson trichrome staining, revealed significant accumulation of fibrotic tissue in the RV of male rats with PH (C), whereas the RV of female rats with PH (D) did not differ from controls (Cont; A, B). Five random fields (40×) for each animal were scored by a blinded observer. Scoring confirmed the development of severe RV fibrosis only in male rats with PH (E). Results are expressed as mean ± SEM; N = 6 rats in each group. Asterisk indicates P < 0.05 versus Cont group. Dagger indicates P < 0.05 versus male PH group. The white bar corresponds to 200 μm.
Figure 8
Figure 8
Caveolin-1 protein levels are decreased in male rats with pulmonary hypertension (PH). Western blot analysis demonstrated that caveolin-1 protein levels were higher in control (Cont) female rates compared with Cont male rats (A). Caveolin-1 protein levels were significantly reduced in male but not female rats with PH (A). Endothelial nitric oxide synthase (eNOS)-mediated superoxide production was also significantly increased in the hearts of male but not female rats with PH (B). Results are expressed as mean ± SEM; N = 3–4 rats in each group. Asterisk indicates P < 0.05 versus Cont group. Dagger indicates P < 0.05 versus male PH group.
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