Inflammation and angiogenesis are key components of fibrovascular tissue growth, a biological event underlying both physiological (wound healing) and pathological conditions (tumor development, chronic inflammation). We investigated these components in three frequently used mouse strains (Swiss, Balb/c and C57BL/6J) to verify the influence of genetic background on the kinetics of inflammatory cell recruitment/activation, neovascularization, extracellular matrix deposition, and cytokine production in polyether-polyurethane sponge implanted subcutaneously in male mice of these strains. The kinetics of neutrophil recruitment/activation as assessed by myeloperoxidase (MPO) activity was 2- and 3-fold higher in Balb/c implants at day 1 compared with Swiss and C57BL/6J implants, respectively. Macrophage accumulation/activation as NAG (n-acetyl β-glucosaminidase) activity was higher in Swiss implants. The levels the monocyte chemoattractant protein 1 (CCL2(MCP-1)) peaked at day 10 in the three types of implants but was produced more by C57BL/6J mice. Angiogenesis (hemoglobin, vascular endothelial growth factor-VEGF, and number of vessels) differed among the strains. Swiss implants had the highest hemoglobin content but the lowest VEGF levels. In contrast, Balb/c implants had higher VEGF levels but lower hemoglobin. Collagen deposition and transforming growth factor β-1; TGFβ-1 levels also varied among the groups. Swiss and Balb/c implants had progressive increase in TGFβ-1 from 4 to 14 days, while C57BL/6J implants achieved the peak at day 10 and fell at day 14. These findings emphasize the major contribution of genetic background in the temporal pattern and intensity of inflammatory angiogenesis components that may have functional consequences in physiological and pathological conditions where these processes co-exist.

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.

Photobiomodulation is being widely applied for improving dermal or mucosal wound healing. However, the underlying cellular and molecular processes that directly contribute to its effects remain poorly understood. Pericytes are relevant cells involved in the wound microenvironment and could be one of the main targets of photobiomodulation due to their plasticity and perivascular localization. Herein, we investigate tissue repair under the photobiomodulation stimulus using a pericyte labeled (or reporter) transgenic mice. Using a model of two contralateral back wounds, one the control and the other photoactivated daily (660 nm, 20 mW, 0.71 W/cm2, 5 J/cm2, 7 s, 0.14 J), we showed an overall influx of immune and undifferentiated cells and higher mobilization of a potent pericyte subpopulation (Type-2 pericytes) in the photoactivated wounds in comparison to the controls. Doppler analysis showed a significant increase in the blood flow in the photoactivated wounds, while marked vascular supply was observed histologically. Histochemical analysis has indicated more advanced stages of tissue repair after photoactivation. These data suggest that photobiomodulation significantly accelerates tissue repair through its vascular effects with direct recruitment of pericytes to the injury site.

Injury of skeletal abdominal muscle wall is a common medical condition and implantation of synthetic or biological material is a procedure to repair musculofascial defects. We proposed to characterize the dynamics of inflammatory cell recruitment, newly formed blood vessels, cytokine production and fibrogenesis in the abdominal skeletal muscle in response to polyether-polyurethane sponge implants in mice. At 2, 4, 7 and 10days after implantation the muscle tissue underneath the sponge matrix was removed for the assessment of the angiogenic response (hemoglobin content, vascular endothelial growth factor and morphometric analysis of the number of vessels) and inflammation (myeloperoxidase and n-acethyl-B-d-glucosaminidase activities, cytokines). In addition, muscle fibrogenesis was determined by the levels of TGF-β1 and collagen deposition. Hemoglobin content, wash out rate of sodium fluorescein (indicative of blood flow) and the number of vessels increased in the abdominal muscle bearing the synthetic matrix in comparison with the intact muscle. Neutrophil recruitment peaked in the muscle at day 2, followed by macrophage accumulation at day 4 post-injury. The levels of the cytokines, VEGF, TNF-α, CCL-2/MCP-1 were higher in the injured muscle compared with the intact muscle and peaked soon after muscle injury (days 2 to 4). Collagen levels were higher in sponge-bearing muscle compared with the non-bearing tissue soon after injury (day 2). The implantation technique together with the inflammatory and vascular parameters used in this study revealed inflammatory, angiogenic and fibrogenic events and mechanisms associated with skeletal muscle responses to synthetic implanted materials.

Butyrate is a short-chain fatty acid (SCFA) derived from microbiota and is involved in a range of cell processes in a concentration-dependent manner. Low concentrations of sodium butyrate (NaBu) was shown to be proangiogenic. However, the mechanisms associated with these effects are not yet fully known. Here, we investigated the contribution of the SCFA receptor GPR43 in the proangiogenic effects of local treatment with NaBu and its effects on matrix remodeling using the sponge-induced fibrovascular tissue model in mice lacking the GPR43 gene (GPR43-KO) and the wild-type (WT). We demonstrated that NaBu (0.2 mM intraimplant) treatment enhanced the neovascularization process, blood flow, and VEGF levels in a GPR43-dependent manner in the implants. Moreover, NaBu was able to modulate matrix remodeling aspects of the granulation tissue such as proteoglycans production, collagen deposition and α-SMA expression in vivo, besides to increase TGF-b1 levels in the fibrovascular tissue, in a GPR43-dependent manner. Interestingly, NaBu directly stimulated L929 murine fibroblasts migration, and TGF-β1 and collagen production in vitro. GPR43 was found to be expressed in human dermal fibroblasts, myofibroblasts and endothelial cells. Overall, our findings evidence that the metabolite-sensing receptor GPR43 contributes to the effects of low dose of NaBu in inducing angiogenesis and matrix remodeling during granulation tissue formation. These data provide important insights for the proposition of new therapeutic approaches based on NaBu, beyond the highly explored intestinal, anti-inflammatory, and anti-cancer purposes, as a local treatment to improve tissue repair, particularly, by modulating granulation tissue components.