RESUMO
Ischemic stroke is a significant global health issue, ranking fifth among all causes of death and a leading cause of serious long-term disability. Ischemic stroke leads to severe outcomes, including permanent brain damage and neuronal dysfunction. Therefore, decreasing and preventing neuronal injuries caused by stroke has been the focus of therapeutic research. In recent years, many studies have shown that fluctuations in hormonal levels influence the prognosis of ischemic stroke. Thus, it is relevant to understand the role of hormones in the pathophysiological mechanisms of ischemic stroke for preventing and treating this health issue. Here, we investigate the contribution of the prolactin/vasoinhibin axis, an endocrine system regulating blood vessel growth, immune processes, and neuronal survival, to the pathophysiology of ischemic stroke. Male mice with brain overexpression of prolactin or vasoinhibin by adeno-associated virus (AAV) intracerebroventricular injection or lacking the prolactin receptor (Prlr-/-) were exposed to transient middle cerebral artery occlusion (tMCAO) for 45 min followed by 48 h of reperfusion. Overexpression of vasoinhibin or the absence of the prolactin receptor led to an increased lesion volume and decreased survival rates in mice following tMCAO, whereas overexpression of prolactin had no effect. In addition, astrocytic distribution in the penumbra was altered, glial fibrillary acidic protein and S100b mRNA expressions were reduced, and interleukin-6 mRNA expression increased in the ischemic hemisphere of mice overexpressing vasoinhibin. Of note, prolactin receptor-null mice (Prlr-/-) showed a marked increase in serum vasoinhibin levels. Furthermore, vasoinhibin decreased astrocyte numbers in mixed hippocampal neuron-glia cultures. These observations suggest that increased vasoinhibin levels may hinder astrocytes' protective reactivity. Overall, this study suggests the involvement of the prolactin/vasoinhibin axis in the pathophysiology of ischemic stroke-induced brain injury and provides insights into the impact of its dysregulation on astrocyte reactivity and lesion size. Understanding these mechanisms could help develop therapeutic interventions in ischemic stroke and other related neurological disorders.
Assuntos
Proteínas de Ciclo Celular , Gliose , Prolactina , Receptores da Prolactina , Animais , Prolactina/metabolismo , Masculino , Camundongos , Gliose/patologia , Gliose/metabolismo , Receptores da Prolactina/metabolismo , Receptores da Prolactina/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Camundongos Endogâmicos C57BL , Astrócitos/metabolismo , Astrócitos/patologia , Camundongos Knockout , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/metabolismoRESUMO
The term inflammatory arthritis defines a family of diseases, including rheumatoid arthritis (RA), caused by an overactive immune system, and influenced by host aspects including sex, reproductive state, and stress. Prolactin (PRL) is a sexually dimorphic, reproductive, stress-related hormone long-linked to RA under the general assumption that it aggravates the disease. However, this conclusion remains controversial since PRL has both negative and positive outcomes in RA that may depend on the hormone circulating levels, synthesis by joint tissues, and complex interactions at the inflammatory milieu. The inflamed joint is rich in matrix metalloproteases that cleave PRL to vasoinhibin, a PRL fragment with proinflammatory effects and the ability to inhibit the hyperpermeability and growth of blood vessels. This review addresses this field with the idea that explanatory mechanisms lie within the PRL/vasoinhibin axis, an integrative framework influencing not only the levels of systemic and local PRL, but also the proteolytic conversion of PRL to vasoinhibin, as vasoinhibin itself has dual actions on joint inflammation. In this review, we discuss recent findings from mouse models suggesting the upregulation of endogenous vasoinhibin by the pro-inflammatory environment and showing dichotomous actions and signaling mechanisms of PRL and vasoinhibin on joint inflammation that are cell-specific and context-dependent. We hypothesize that these opposing actions work together to balance the inflammatory response and provide new insights for understanding the pathophysiology of RA and the development of new treatments.
Assuntos
Artrite Reumatoide , Prolactina , Animais , Inflamação , Camundongos , Prolactina/metabolismo , Ligação ProteicaRESUMO
The hormone prolactin (PRL) is emerging as an important regulator of ocular blood vessels. PRL is pro-angiogenic and acquires anti-angiogenic properties after undergoing proteolytic cleavage to the PRL fragment, vasoinhibin. The vascularisation of the rodent retina develops after birth when it rapidly expands until completion at the end of the first postnatal week. Exposure of newborn mice to high oxygen levels lowers the rate of blood vessel growth. In the present study, we investigated whether PRL treatment modifies the vascularisation of the retina in newborn mice exposed to high oxygen or to normoxia and whether the retinal conversion of PRL to vasoinhibin may be altered in the neonate. Newborn mice and their nursing mothers were subjected to 75% oxygen or to normoxia from postnatal day (P) 6 to P8 (group 1) or from P2 to P5 (group 2). PRL (2 µg g-1 , i.p., twice a day) or vehicle was injected from P5 to P8 in group 1 and from P1 to P5 in group 2. PRL treatment reduced the retinal inhibition of blood vessel growth and the increase in vascular regression induced by hyperoxia as revealed by immunofluorescence staining of blood vessels and the expression of angiogenesis and apoptosis markers. The pro-angiogenic effect may involve a reduced conversion of PRL to vasoinhibin. Incubation of PRL with retinal extracts showed reduced activity of the PRL-cleaving protease, cathepsin D, in the neonate vs the adult retina that was further reduced under hyperoxia. PRL and the PRL receptor mRNA were expressed at higher levels in the retina at P8 than in the adult, whereas endogenous PRL was undetectable in the circulation at P8. We conclude that PRL has a pro-angiogenic effect in the neonate retina as a result of its reduced conversion to vasoinhibin and that PRL produced by the retina may help promote physiological vascularisation after birth.
Assuntos
Hiperóxia , Neovascularização Fisiológica , Prolactina , Vasos Retinianos , Animais , Feminino , Masculino , Camundongos , Gravidez , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Hiperóxia/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Prolactina/sangue , Prolactina/metabolismo , Prolactina/farmacologia , Receptores da Prolactina/efeitos dos fármacos , Receptores da Prolactina/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/crescimento & desenvolvimento , Retinopatia da Prematuridade/patologiaRESUMO
Morphological and behavioral evidence suggests that vasoinhibin is present in the central nervous system (CNS), triggering neuroendocrine and behavioral responses to stress. Moreover, vasoinhibin reduces neuronal survival and differentiation of primary sensory neurons of the peripheral nervous system. To address the functional role played by vasoinhibin at the CNS, and to better understand the underlying mechanisms involved in its actions, we treated primary cultured hippocampal neurons obtained from embryonic day 16 (E16) mice with a human recombinant vasoinhibin. We examined the resulting cellular changes, focusing on neuronal cell death, and explored the local generation of vasoinhibin within the hippocampus. Our results show that vasoinhibin significantly reduced neuronal cell density and increased immunoreactive activated caspase-3 and TUNEL-positive staining at 72, 16, and 24 h, respectively. Furthermore, vasoinhibin increased the expression of proapoptotic genes BAX, BAD, BIM, and PUMA and decreased that of the antiapoptotic gene BCL-2 at 24 h, as assessed by quantitative real-time reverse transcription-polymerase chain reaction. Vasoinhibin effects were blocked by coincubation with a vasoinhibin antibody or with prolactin. Immunoreactive bands consistent with vasoinhibin were observed in hippocampal extracts by Western blot analysis, and a prolactin standard was cleaved to vasoinhibin by a hippocampal lysate in a heat- and cathepsin D inhibitor pepstatin A-dependent fashion. Taken together, these data support the notion that vasoinhibin is locally produced by cathepsin D within the embryonic mouse hippocampus, a brain region that plays a critical role in emotional regulation, resulting in decreased neuronal cell viability via the activation of the intrinsic apoptosis pathway.