BACKGROUND AND PURPOSEAVE 0991 (AVE) is a non-peptide compound, mimic of the angiotensin (Ang)-(1-7) actions in many tissues and pathophysiological states. Here, we have investigated the effect of AVE on pulmonary remodelling in a murine model of ovalbumin (OVA)-induced chronic allergic lung inflammation. EXPERIMENTAL APPROACHWe used BALB/c mice (6-8 weeks old) and induced chronic allergic lung inflammation by OVA sensitization (20 μg·mouse −1 , i.p., four times, 14 days apart) and OVA challenge (1%, nebulised during 30 min, three times per·week, for 4 weeks). Control and AVE groups were given saline i.p and challenged with saline. AVE treatment (1 mg·kg −1 ·per day, s.c.) or saline (100 μL·kg −1 ·per day, s.c.) was given during the challenge period. Mice were anaesthetized 72 h after the last challenge and blood and lungs collected. In some animals, primary bronchi were isolated to test contractile responses. Cytokines were evaluated in bronchoalveolar lavage (BAL) and lung homogenates. KEY RESULTSTreatment with AVE of OVA sensitised and challenged mice attenuated the altered contractile response to carbachol in bronchial rings and reversed the increased airway wall and pulmonary vasculature thickness and right ventricular hypertrophy. Furthermore, AVE reduced IL-5 and increased IL-10 levels in the BAL, accompanied by decreased Ang II levels in lungs. CONCLUSIONS AND IMPLICATIONSAVE treatment prevented pulmonary remodelling, inflammation and right ventricular hypertrophy in OVA mice, suggesting that Ang-(1-7) receptor agonists are a new possibility for the treatment of pulmonary remodelling induced by chronic asthma.

The microvasculature heterogeneity is a complex subject in vascular biology. The difficulty of building a dynamic and interactive view among the microenvironments, the cellular and molecular heterogeneities, and the basic aspects of the vessel formation processes make the available knowledge largely fragmented. The neovascularisation processes, termed vasculogenesis, angiogenesis, arteriogenesis, and lymphangiogenesis, are important to the formation and proper functioning of organs and tissues both in the embryo and the postnatal period. These processes are intrinsically related to microvascular cells, such as endothelial and mural cells. These cells are able to adjust their activities in response to the metabolic and physiological requirements of the tissues, by displaying a broad plasticity that results in a significant cellular and molecular heterogeneity. In this review, we intend to approach the microvasculature heterogeneity in an integrated view considering the diversity of neovascularisation processes and the cellular and molecular heterogeneity that contribute to microcirculatory homeostasis. For that, we will cover their interactions in the different blood-organ barriers and discuss how they cooperate in an integrated regulatory network that is controlled by specific molecular signatures.

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Introduction: Angiotensin-(1-7) is known by its cardiovascular protective effects by activating MAS receptor. It has been shown that Angiotensin-(1-7) stimulates proliferation of endothelial progenitor cells in vitro, but exerts antiangiogenic effects both in inflammatory and tumor environments in vivo. The role of Angiotensin-(1-7)-MAS axis on ischemic conditions was never reported. Hypothesis: We assessed the hypothesis that MAS receptor signaling plays a role in reparative neovascularization after hindlimb ischemia in mice. METHODS: C57BL/6 wild-type (WT) and MAS receptor knockout (MAS-KO) mice (8-10 weeks) were subjected to unilateral permanent left femoral artery occlusion (FAO). Hindlimb blood flow was measured before and immediately after FAO, and 7 and 14 days after FAO by laser Doppler perfusion imaging (LDPI).To further assess the vascularization in the ischemic limb, 28 days after FAO, we used the technique of microbubles contrast enhanced ultrasound perfusion imaging that enables a more sensitive discrimination of blood flow in deep microvessels. Capillary and arteriole density were evaluated by histological analysis at day 14 after FAO. Results: Vascular density was similar in normoperfused muscles from MAS-KO and WT mice. However, the neovascularization response to hindlimb ischemia was significantly reduced in MAS-KO muscles at capillary (p<0.05; n=4/group) and arteriole (p<0.05; n=4/group) level, which led to lesser perfusion recovery of the ischemic limb of MAS-KO mice as evaluated by LDPI (Day 7: 0.67±0.04 vs 0.85±0.04 ischemic/contralateral ratio, p <0.01; Day 14: 0.62±0.15 vs 0.91±0.03, p<0.001; n=8-12/group). In accordance, we observed that MAS-KO mice require shorter time to peak enhancement of microbubles contrast in ischemic adductor muscles compared with WT mice (p<0.01; n = 5-6/group). Conclusion: In conclusion, our data suggests that post-ischemic hindlimb neovascularization and blood flow recovery are impaired in Angiotensin-(1-7)-MAS receptor knockout mice.