Erectile dysfunction (ED) is another manifestation of vascular disease. We evaluated the natural history of ED in the spontaneously hypertensive rat (SHR) and the respective participation of associated pathophysiological modifications, i.e., endothelial dysfunction and tissue remodeling. SHR and their normotensive counterparts [Wistar-Kyoto rats (WKY)] of 6, 12, and 24 wk of age (n = 12) were used to evaluate erectile function, erectile and aortic tissue reactivity, and remodeling. Erectile responses in SHR are reduced at all ages (P < 0.001). In both aortic and erectile tissues of SHR and WKY, relaxations to ACh are altered progressively with age, although more markedly in SHR. They are decreased at 12 wk of age in erectile tissue of SHR compared with WKY (maximal relaxation: -19.2 +/- 2.8% vs. -28.3 +/- 3.9%, P < 0.001) but only at 24 wk of age in aortas (-47.9 +/- 6.4% vs. -90.5 +/- 2.9%, P < 0.001). Relaxations to sodium nitroprusside are unaltered in aortic rings of both strains but enhanced in erectile tissue of SHR at 12 wk of age. Major modifications in the distribution of collagen I, III, and V in SHR occur in both types of tissue and are detectable sooner in erectile tissue compared with aortic tissue. The onset of ED is detectable before the onset of hypertension in the SHR. Structural and functional alterations, while similar, occur earlier in erectile compared with vascular tissue. If confirmed in humans, ED could be an early warning sign for hypertension, and common therapeutic strategies targeting both ED and hypertension could be investigated.

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Fibrosis is an unregulated tissue repair process whose predominant characteristics are the proliferation of myofibroblasts and an excessive deposition of extracellular matrix. Transforming growth factor (TGF)-beta1 is considered as one of the most fibrogenic cytokines. However, the molecular mechanisms involved in its profibrotic role are not fully understood. Here, we addressed the role of TGF-beta1 on cell proliferation and intracellular signal transduction in a pig model of skin fibrosis induced by gamma-irradiation. Primary myofibroblasts were isolated from the fibrotic tissue and their response to TGF-beta1 was compared to that of normal skin fibroblasts. The present results show that the differentiation of myofibroblasts involves a lack of TGF-beta1 growth inhibition and an impaired TGF-beta1 signaling. Receptor activity and Smad2/4 or Smad3/4 complex formation were similar in both cell types after TGF-beta1 treatment. However, the translocation of Smad3 protein into the nucleus was reduced in myofibroblasts as compared to that in fibroblasts, as well as its binding to target DNA sequences and the activation of the Smad binding elements found in the PAI-1. Interestingly, Smad2 was translocated similarly to the nucleus in both cell types suggesting that this protein may function normally in myofibroblasts. We propose that uncoupling of antiproliferative and profibrotic actions of TGF-beta1 in fibrosis may occur through differential regulation of the activities of Smad2 and Smad3 transcription factors.