Canonical signaling by TGF family members in mesenchymal stromal cells is dispensable for hematopoietic niche maintenance under basal and stress conditions.

Mesenchymal stromal cells are an important component of the bone marrow hematopoietic niche. Prior studies showed that signaling from members of the transforming growth factor (TGF) superfamily in mesenchymal stromal cells is required for normal niche development. Here, we assessed the impact of TGF family signaling on niche maintenance and stress responses by deleting Smad4 in mesenchymal stromal cells at birth, thereby abrogating canonical TGF signaling. No alteration in the number or spatial organization of CXCL12-abundant reticular (CAR) cells, osteoblasts, or adipocytes was observed in Osx-Cre, Smad4fl/fl mice, and expression of key niche factors was normal. Basal hematopoiesis and stress erythropoiesis responses to acute hemolytic anemia were normal. TGF-ß potently inhibits stromal CXCL12 expression in vitro; however, G-CSF induced decreases in bone marrow CXCL12 expression and subsequent hematopoietic stem/progenitor cell mobilization were normal in Osx-Cre, Tgfbr2fl/fl mice, in which all TGF-ß signaling in mesenchymal stromal is lost. Finally, although a prior study showed that TGF-ß enhances recovery from myeloablative therapy, hematopoietic recovery following single or multiple doses of 5-flurauracil were normal in Osx-Cre, Tgfbr2fl/fl mice. Collectively, these data suggest that TGF family member signaling in mesenchymal stromal cells is dispensable for hematopoietic niche maintenance under basal and stress conditions.

Stromal reprogramming: A target for tumor therapy.

Cancer associated fibroblasts (CAFs) as the dominant, long-lived and highly plastic cells within the tumor microenvironment (TME) with multi-faceted roles that are endowed with tumor aggressive features. They can instruct and shape the stroma of tumor into being a highly qualified bed for cellular recruitment, differentiation and plasticity in the host tissue or secondary organ/s. In this Review, we have a discussion over CAF reprogramming as a general concept, inducers and outcomes, pursued by suggesting potential strategies to combat this key promoter of tumor.

Effect of Negative Pressure Wound Therapy on Cellular Fibronectin and Transforming Growth Factor-ß1 Expression in Diabetic Foot Wounds.

BACKGROUND: Chronic diabetic foot wounds are a leading cause of amputation, morbidity, and hospitalization for patients with diabetes. Negative-pressure wound therapy (NPWT) can putatively facilitate wound healing, but the underlying mechanisms remain unclear. Cellular fibronectin (cFN) and transforming growth factor-ß1 (TGF-ß1) play an important role in wound healing. This prospective randomized controlled trial evaluated the effects of NPWT on the production of cFN and the expression of TGF-ß1 in diabetic foot wounds of patients. METHODS: From January 2012 to January 2015, 40 patients with diabetic foot wounds were randomly and equally apportioned to receive either NPWT or advanced moist wound therapy (control) for 7 days. Granulation tissue was harvested before and after treatment. Immunohistochemistry and Western blot were performed to evaluate protein levels of cFN and TGF-ß1, and real-time polymerase chain reaction (PCR) to measure corresponding mRNA expressions. RESULTS: NPWT facilitated the expression of cFN and TGF-ß1 in diabetic foot wounds. Immunohistochemical analysis revealed higher levels of cFN and TGF-ß1 in the NPWT group than in the control group. Western blot and real-time PCR analysis further showed that protein and mRNA levels of cFN or TGF-ß1 were higher in the NPWT group than that in the control group ( P < .01, both). CONCLUSION: Our results showed that NPWT facilitated the production of cFN and the expression of TGF-ß1 in granulation tissue in diabetic foot ulcers. LEVEL OF EVIDENCE: Level I, randomized controlled study.

Loss of microRNA-17∼92 in smooth muscle cells attenuates experimental pulmonary hypertension via induction of PDZ and LIM domain 5.

RATIONALE: Recent studies suggest that microRNAs (miRNAs) play important roles in regulation of pulmonary artery smooth muscle cell (PASMC) phenotype and are implicated in pulmonary arterial hypertension (PAH). However, the underlying molecular mechanisms remain elusive. OBJECTIVES: This study aims to understand the mechanisms regulating PASMC proliferation and differentiation by microRNA-17∼92 (miR-17∼92) and to elucidate its implication in PAH. METHODS: We generated smooth muscle cell (SMC)-specific miR-17∼92 and PDZ and LIM domain 5 (PDLIM5) knockout mice and overexpressed miR-17∼92 and PDLIM5 by injection of miR-17∼92 mimics or PDLIM5-V5-His plasmids and measured their responses to hypoxia. We used miR-17∼92 mimics, inhibitors, overexpression vectors, small interfering RNAs against PDLIM5, Smad, and transforming growth factor (TGF)-ß to determine the role of miR-17∼92 and its downstream targets in PASMC proliferation and differentiation. MEASUREMENTS AND MAIN RESULTS: We found that human PASMC (HPASMC) from patients with PAH expressed decreased levels of the miR-17∼92 cluster, TGF-ß, and SMC markers. Overexpression of miR-17∼92 increased and restored the expression of TGF-ß3, Smad3, and SMC markers in HPASMC of normal subjects and patients with idiopathic PAH, respectively. Knockdown of Smad3 but not Smad2 prevented miR-17∼92-induced expression of SMC markers. SMC-specific knockout of miR-17∼92 attenuated hypoxia-induced pulmonary hypertension (PH) in mice, whereas reconstitution of miR-17∼92 restored hypoxia-induced PH in these mice. We also found that PDLIM5 is a direct target of miR-17/20a, and hypertensive HPASMC and mouse PASMC expressed elevated PDLIM5 levels. Suppression of PDLIM5 increased expression of SMC markers and enhanced TGF-ß/Smad2/3 activity in vitro and enhanced hypoxia-induced PH in vivo, whereas overexpression of PDLIM5 attenuated hypoxia-induced PH. CONCLUSIONS: We provided the first evidence that miR-17∼92 inhibits PDLIM5 to induce the TGF-ß3/SMAD3 pathway, contributing to the pathogenesis of PAH.

Role of 20-HETE in the impaired myogenic and TGF responses of the Af-Art of Dahl salt-sensitive rats.

The present study examined whether 20-HETE production is reduced in the renal vasculature and whether this impairs myogenic or tubuloglomerular feedback (TGF) responses of the afferent arteriole (Af-Art). The production of 20-HETE was 73% lower in renal microvessels of Dahl salt-sensitive rats (SS) rats than in SS.5(BN) rats, in which chromosome 5 from the Brown Norway (BN) rat containing the CYP4A genes was transferred into the SS genetic background. The luminal diameter of the Af-Art decreased by 14.7 ± 1.5% in SS.5(BN) rats when the perfusion pressure was increased from 60 to 120 mmHg, but it remained unaltered in SS rats. Administration of an adenosine type 1 receptor agonist (CCPA, 1 µM) reduced the diameter of the Af-Art in the SS.5(BN) rats by 44 ± 2%, whereas the diameter of the Af-Art of SS rats was unaltered. Autoregulation of renal blood flow (RBF) and glomerular capillary pressure (PGC) was significantly impaired in SS rats but was intact in SS.5(BN) rats. Administration of a 20-HETE synthesis inhibitor, HET0016 (1 µM), completely blocked the myogenic and adenosine responses in the Af-Art and autoregulation of RBF and PGC in SS.5(BN) rats, but it had no effect in SS rats. These data indicate that a deficiency in the formation of 20-HETE in renal microvessels impairs the reactivity of the Af-Art of SS rats and likely contributes to the development of hypertension induced renal injury.

Common fibroid-associated genes are differentially expressed in phenotypically dissimilar cell populations isolated from within human fibroids and myometrium.

Uterine fibroids are a prevalent gynaecological condition in reproductive-aged women and are the commonest reason for hysterectomy. The cellular composition of clonal fibroids are heterogeneous, with phenotypically dissimilar cells that include smooth muscle cells (SMC), vascular SMC (VSMC) and fibroblasts. The aim of our study was to investigate genes that are commonly differentially expressed between fibroid and myometrial whole tissues in phenotypically different sub-populations of cells isolated from fibroid and myometrium. Genes to be investigated by fluorescence-activated cell sorting, quantitative real-time PCR and immunocytochemistry include transforming growth factor ß (TGFB) and retinoic acid (RA) signalling families and steroid hormone receptors. We hypothesised that each cell population isolated from fibroid and myometrium would differ in the expression of fibroid-associated genes. We demonstrated that phenotypically different cellular constituents of uterine fibroids differentially express cellular RA-binding protein 2 (CRABP2), progesterone receptor B (PRB) and TGFB receptor 2 mRNA in fibroid-derived cells of VSMC and SMC phenotype. CRABP2 mRNA was also differentially expressed in fibroblasts and VSMC sub-populations from within clonal fibroid tumours. We conclude that differential regulation of RA, TGFB and PR pathway transcription occurs in fibroid-associated SMC and -fibroblasts and that investigation of paracrine interactions between different cell types within the fibroid microenvironment provides an important new paradigm for understanding the pathophysiology of this common disease.

Multifunctional bone morphogenetic protein system in endocrinology.

New biological activities of bone morphogenetic proteins (BMPs) in the endocrine system have recently been revealed. The BMP system is composed of approximately 30 ligands and preferential combinations of type I and type II receptors. The BMP system not only induces bone formation but also plays unique tissue-specific roles in various organs. For instance, the ovarian BMP system is a physiological inhibitor of luteinization in growing ovarian follicles. In the ovary, the expression of oocyte-derived BMP-15 is critical for female reproduction. In the pituitary, BMP-4 is a key player for initial development of the anterior pituitary, while it is also functionally involved in some differentiated pituitary tumors, including prolactinoma and Cushing's disease. In the adrenal glands, BMP-6 and BMP-4 modulate aldosterone and catecholamine production, respectively, which contributes to a functional interaction between the cortex and medulla. In the present review, recent advances in BMP biology in the field of endocrinology are described and the possibility for clinical application of BMP activity is discussed.

Human immunodeficiency virus enhances hepatitis C virus replication by differential regulation of IFN and TGF family genes.

HIV co-infection significantly impacts the natural history of hepatitis C virus (HCV) by increasing plasma HCV viral load, accelerating liver disease progression, and reducing rates of HCV clearance. Cytokines play an important role in regulating hepatic inflammation and fibrogenesis during chronic HCV infection, yet the impact of HIV on cytokine expression is unknown. In this study, an HCV continuous infection cell culture system was modified to permit co-infection with HIV to test the hypothesis that virus-induced disregulation of immune-response genes, particularly interferons and TGF-ß, may create a permissive environment for the initial establishment of HIV/HCV co-infection in the host. CCR5-expressing Huh-7.5 hepatoma cells were transduced with human CD4 antigen to allow HIV infection in vitro. Co-infection of CD4⁺ Huh-7.5 cells with HIV and HCV or co-culture of HIV-infected CD4⁺ Huh-7.5 cells and HCV-infected Huh-7.5 cells increased the level of HCV RNA compared to HCV mono-infection. Quantitative gene expression analysis revealed HIV-induced up regulation of most tested IFN family genes when compared to HCV or co-infection. HCV infection induced up regulation of many TGF family genes that were subsequently down-regulated in the presence of HIV or HIV/HCV. Interestingly, co-infection resulted in down regulation of several IFN genes and significant up regulation of TGF-ß genes leading to an overall enhancement of HCV replication. These data suggest that HIV infection may influence HCV replication in vitro by increasing levels of HCV RNA, possibly through the differential regulation of endogenous IFN and TGF family genes.

Role of connexin40 in the autoregulatory response of the afferent arteriole.

Connexins in renal arterioles affect autoregulation of arteriolar tonus and renal blood flow and are believed to be involved in the transmission of the tubuloglomerular feedback (TGF) response across the cells of the juxtaglomerular apparatus. Connexin40 (Cx40) also plays a significant role in the regulation of renin secretion. We investigated the effect of deleting the Cx40 gene on autoregulation of afferent arteriolar diameter in response to acute changes in renal perfusion pressure. The experiments were performed using the isolated blood perfused juxtamedullary nephron preparation in kidneys obtained from wild-type or Cx40 knockout mice. Renal perfusion pressure was increased in steps from 75 to 155 mmHg, and the response in afferent arteriolar diameter was measured. Hereafter, a papillectomy was performed to inhibit TGF, and the pressure steps were repeated. Conduction of intercellular Ca(2+) changes in response to local electrical stimulation was examined in isolated interlobular arteries and afferent arterioles from wild-type or Cx40 knockout mice. Cx40 knockout mice had an impaired autoregulatory response to acute changes in renal perfusion pressure compared with wild-type mice. Inhibition of TGF by papillectomy significantly reduced autoregulation of afferent arteriolar diameter in wild-type mice. In Cx40 knockout mice, papillectomy did not affect the autoregulatory response, indicating that these mice have no functional TGF. Also, Cx40 knockout mice showed no conduction of intercellular Ca(2+) changes in response to local electrical stimulation of interlobular arteries, whereas the Ca(2+) response to norepinephrine was unaffected. These results suggest that Cx40 plays a significant role in the renal autoregulatory response of preglomerular resistance vessels.

Avaliação da eficácia de diferentes protocolos de preparo do Plasma Rico em Plaquetas para uso em Medicina Equina / Evaluating the effectiveness of different protocols for preparation of platelet rich plasma for use in equine medicine

O Plasma Rico em Plaquetas (PRP) é um preparado do sangue total que contém diversos fatores de crescimento responsáveis pela proliferação e diferenciação celular, angiogênese, como também pelo aumento da produção da matriz extracelular. Nesse sentido, o objetivo do presente estudo foi testar 10 protocolos diferentes de centrifugação para obtenção de PRP a partir do sangue total de equinos hígidos. Para isso foram utilizadas 10 amostras de 27mL de sangue total de cinco animais, as quais foram centrifugadas conforme cada protocolo proposto. Os resultados revelaram que os protocolos com menor força de centrifugação relativa resultaram em maior (p<0,05) concentração de plaquetas e, que não houve (p>0,05) influência do tempo de centrifugação em relação a essa variável. A influência do tempo foi observada apenas no número de leucócitos em protocolos com menor força de centrifugação relativa (FCR). Os quatro melhores protocolos, que obtiveram as maiores concentrações de plaquetas, foram submetidos à análise pelo teste de ELISA para dosar a quantidade de TGF-β que não revelou diferença (p>0,05) entre os protocolos.

Platelet-rich plasma (PRP) is a prepared of the whole blood which contains several growth factors responsible for cellular proliferation and differentiation, angiogenesis, and for the increase of the extracellular matrix. Thus, the aim of this study was to test 10 different centrifugation protocols to obtain PRP from the whole blood of healthy equines. Ten samples of 27mL of the whole blood of 5 healthy equines were used, which were centrifuged in accordance to the proposed protocols. The results showed that the protocols with less relative centrifugation force resulted in greater (p<0,05) platelets concentration. Also, platelets concentration was not influenced by varying the time of centrifugation. However, time did affect the number of leukocytes in some protocols. The best four protocols were analyzed by ELISA test to quantitate the amount of TGF-β, which revealed no difference (p> 0.05) between the protocols.

BMP2 signals loss of epithelial character in epicardial cells but requires the Type III TGFß receptor to promote invasion.

Coronary vessel development depends on a subpopulation of epicardial cells that undergo epithelial to mesenchymal transformation (EMT) and invade the subepicardial space and myocardium. These cells form the smooth muscle of the vessels and fibroblasts, but the mechanisms that regulate these processes are poorly understood. Mice lacking the Type III Transforming Growth Factor ß Receptor (TGFßR3) die by E14.5 due to failed coronary vessel development accompanied by reduced epicardial cell invasion. BMP2 signals via TGFßR3 emphasizing the importance of determining the relative contributions of the canonical BMP signaling pathway and TGFßR3-dependent signaling to BMP2 responsiveness. Here we examined the role of TGFßR3 in BMP2 signaling in epicardial cells. Whereas TGFß induced loss of epithelial character and smooth muscle differentiation, BMP2 induced an ALK3-dependent loss of epithelial character and modestly inhibited TGFß-stimulated differentiation. Tgfbr3(-/-) cells respond to BMP2 indicating that TGFßR3 is not required. However, Tgfbr3(-/-) cells show decreased invasion in response to BMP2 and overexpression of TGFßR3 in Tgfbr3(-/-) cells rescued invasion. Invasion was dependent on ALK5, ALK2, ALK3, and Smad4. Expression of TGFßR3 lacking the 3 C-terminal amino acids required to interact with the scaffolding protein GIPC (GAIP-interacting protein, C terminus) did not rescue. Knockdown of GIPC in Tgfbr3(+/+) or Tgfbr3(-/-) cells rescued with TGFßR3 decreased BMP2-stimulated invasion confirming a requirement for TGFßR3/GIPC interaction. Our results reveal the relative roles of TGFßR3-dependent and TGFßR3-independent signaling in the actions of BMP2 on epicardial cell behavior and demonstrate the critical role of TGFßR3 in mediating BMP2-stimulated invasion.

Cutaneous scarring: Pathophysiology, molecular mechanisms, and scar reduction therapeutics Part I. The molecular basis of scar formation.

Cutaneous scarring is often the epicenter of patient-related concerns, and the question "Will there be a scar?" is one that is all too familiar to the everyday clinician. In approaching this topic, we have reviewed the pathology, the embryology, and the molecular biology of cutaneous scarring.

TGF-ß suppresses ß-catenin-dependent tolerogenic activation program in dendritic cells.

The mechanisms that underlie the critical dendritic cell (DC) function in maintainance of peripheral immune tolerance are incompletely understood, although the ß-catenin signaling pathway is critical for this role. The molecular details by which ß-catenin signaling is regulated in DCs are unknown. Mechanical disruption of murine bone marrow-derived DC (BMDC) clusters activates DCs while maintaining their tolerogenic potential and this activation is associated with ß-catenin signaling, providing a useful model with which to explore tolerance-associated ß-catenin signaling in DCs. In this report, we demonstrate novel molecular features of the signaling events that control DC activation in response to mechanical stimulation. Non-canonical ß-catenin signaling is an essential component of this tolerogenic activation and is modulated by adhesion molecules, including integrins. This unique ß-catenin-dependent signaling pathway is constitutively active at low levels, suggesting that mechanical stimulation is not necessarily required for induction of this unique activation program. We additionally find that the immunomodulatory cytokine TGF-ß antagonizes ß-catenin in DCs, thereby selectively suppressing signaling associated with tolerogenic DC activation while having no impact on LPS-induced, ß-catenin-independent immunogenic activation. These findings provide new molecular insight into the regulation of a critical signaling pathway for DC function in peripheral immune tolerance.

The therapeutic potential of oxygen tension manipulation via hypoxia inducible factors and mimicking agents in guided bone regeneration. A review.

Intraoral bone grafting is routinely employed for implant site development prior or simultaneously to implant placement. Bone graft consolidation is a complex biological process depending on the formation of blood vessels into the augmented area. It is highly regulated by the angiogenesis and osteogenesis coupling phenomenon. The vascular system apart from supplying nutrients and oxygen to the developing and regenerating bone, also delivers critical signals which stimulate mesenchymal cell differentiation towards an osteogenic phenotype. Hypoxia inducible factors (HIFs) and mimicking agents (HMAs) (or alternatively HIF stabilizing agents) are considered to act as key stimulators of blood vessel formation. Under normoxia, HIFs are rapidly degraded. However, their degradation is prevented under hypoxia, which in turn, triggers angiogenesis. Hence, the major role of HMAs is to prevent degradation of HIFs under normoxic conditions. Recent studies suggest that HIFs and HMAs trigger the initiation and promotion of angiogenic-osteogenic cascade events. In vitro and animal studies involving genetic manipulation of individual components of the HIFs and HMAs have provided clues to how angiogenic-osteogenic coupling is achieved. Evidence from preclinical studies further suggests that topical application of HMAs enhance angiogenesis in intraoral augmented sites. In this article, we review the current understanding of the cellular and molecular mechanisms responsible for angiogenic-osteogenic coupling. We also discuss the therapeutic manipulation of HIFs and HMAs in intraoral bone repair and regeneration. Such discoveries suggest promising approaches for the development of novel therapies to improve intraoral bone repair and regeneration procedures.

The physiological role of endoglin in the cardiovascular system.

Endoglin (CD105) is an integral membrane glycoprotein that serves as a coreceptor for members of the transforming growth factor-ß superfamily of proteins. A major role for endoglin in regulating transforming growth factor-ß-dependent vascular remodeling and angiogenesis has been postulated based on the following: 1) endoglin is the gene mutated in hereditary hemorrhagic telangiectasia type 1, a disease characterized by vascular malformations; 2) endoglin knockout mice die at midgestation because of defective angiogenesis; 3) endoglin is overexpressed in neoangiogenic vessels, during inflammation, and in solid tumors; and 4) endoglin regulates the expression and activity of endothelial nitric oxide synthase, which is involved in angiogenesis and vascular tone. Besides the predominant form of the endoglin receptor (long endoglin isoform), two additional forms of endoglin have been recently reported to play a role in the vascular pathology and homeostasis: the alternatively spliced short endoglin isoform and a soluble endoglin form that is proteolytically cleaved from membrane-bound endoglin. The purpose of this review is to underline the role that the different forms of endoglin play in regulating angiogenesis, vascular remodeling, and vascular tone, as well as to analyze the molecular and cellular mechanisms supporting these effects.

Immune factors in human embryo culture and their significance.

There is increasing evidence that human development before implantation is regulated by embryonically and maternally derived growth factors. The "regulators" of embryonic origin such as soluble human leukocyte antigen G, platelet-activating factor, Th1/Th2 cytokines, insulin-like growth factor, epidermal growth factor, transforming growth factor alpha, colony-stimulating factor, platelet-derived growth factor may be used as indicators of embryo viability and implantation potential. The data prove the influence of growth factors on the development and growth of preimplantation embryos. Though there is a lot of research in the field of biomarkers during folliculogenesis and maternal-fetal interface, only few of them deal with regulators derived from embryonic cells to the cultivation medium. The aim of our study was to summarize the research dealing with immune markers produced by embryos in vitro and to estimate their impact on the cell growth, viability and implantation potential.

The CCN family proteins in carcinogenesis.

The CCN (Cyr61 (cysteine-rich protein 61), CTGF (connective tissue growth factor), Nov (nephroblastoma overexpressed)) family consists of six members that belong to matricellular proteins of extracellular matrix (ECM). Like other matricellular proteins, CCN members do not primarily have a structural role; however, they modulate cell-ECM interactions. In general, CCN proteins are formed by four characteristic domain structures and thought to participate in various biological phenomena such as organ development, wound healing, angiogenesis, fibrosis, etc. In cancer, CCN proteins family expresses aberrantly; probably depending on the sites and types, expressions of different CCN proteins have been documented to be linked with either progression or inhibition of the pathological processes of cancer. Through various mechanisms like cell survival, apoptosis, inflammation, cell adhesion and migration and connection with several cytokines, CCN proteins perhaps influence the disease course including tumor metastasis. A majority of the above-mentioned effects are believed to be mediated by binding with integrins, a class of receptors that mediate cell-cell and cell-ECM interactions. Furthermore, the members of CCN family modulate the functions of several important growth factors and related pathways such as insulin-like growth factor (IGF), transforming growth factor-beta (TGF-beta) and Wnt signaling. Interestingly, a variety of factors/proteins linked with these signaling systems are reported to be associated with the carcinogenic process. Nevertheless, a precise knowledge about the pathophysiological activities including signaling pathways of CCN proteins would be helpful to identify molecular targets in order to design therapeutic strategies in the management of cancer.

The role of the epithelium in airway remodeling in asthma.

The bronchial epithelium is the barrier to the external environment and plays a vital role in protection of the internal milieu of the lung. It functions within the epithelial-mesenchymal trophic unit to control the local microenvironment and help maintain tissue homeostasis. However, in asthma, chronic perturbation of these homeostatic mechanisms leads to alterations in the structure of the airways, termed remodeling. Damage to the epithelium is now recognized to play a key role in driving airway remodeling. We have postulated that epithelial susceptibility to environmental stress and injury together with impaired repair responses results in generation of signals that act on the underlying mesenchyme to propagate and amplify inflammatory and remodeling responses in the submucosa. Many types of challenges to the epithelium, including pathogens, allergens, environmental pollutants, cigarette smoke, and even mechanical forces, can elicit production of mediators by the epithelium, which can be translated into remodeling responses by the mesenchyme. Several important mediators of remodeling have been identified, most notably transforming growth factor-beta, which is released from damaged/repairing epithelium or in response to inflammatory mediators, such as IL-13. The cross talk between the epithelium and the underlying mesenchyme to drive remodeling responses is considered in the context of subepithelial fibrosis and potential pathogenetic mechanisms linked to the asthma susceptibility gene, a disintegrin and metalloprotease (ADAM)33.

New insights into target organ involvement in hypertension.

Hypertension and its sequelae are complex processes. Optimization of the care of the hypertensive patient requires not only attention to the regulation of arterial pressure but also attention to blunting the hypertension-related processes that lead to vascular disease. It is clear that the regulation of these processes is much more complex than previously understood. Here several new insights into the pathogenesis of hypertension-related vascular disease have been explored. While this review is not exhaustive, it does serve to point out the varied nature of the biologic processes that must be taken into account and it points to new avenues for the development of therapeutic agents.

The TGFBeta pathway as a therapeutic target in cancer

The TGFBeta pathway has recently emerged as a putative therapeutic target against cancer. However, TGFBeta has a complex and dual role in cancer. In normal epithelial cells and early tumours, TGFBeta acts as a tumour suppressor. In contrast, during tumour progression TGFBeta becomes an oncogenic factor inducing proliferation, angiogenesis, invasion and metastasis, as well as suppressing the anti-tumoral immune response. The role of TGFBeta in oncogenesis requires the precise understanding of the TGFBeta pathway in order to design optimal therapeutic approaches and select the patient population that may benefit from an anti-TGFBeta therapy. Here we review the rationale for evaluating TGFBeta signalling inhibitors as cancer therapeutics, and the progress made in the preclinical and clinical testing of anti- TGFBeta compounds (AU)