Gremlin-1 potentiates the dedifferentiation of VSMC in early stages of atherosclerosis.

Vascular smooth muscle cells (VSMC) are highly specialized, and exhibit a contractile phenotype when mature and fully differentiated, being responsible for vessel homeostasis and blood pressure control. In response to pro-atherogenic stimuli VSMC alter their state of differentiation, increase proliferation and migration, resulting in SMC phenotypes ranging from contractile to synthetic. This variability is observed in cell morphology and expression level of marker genes for differentiation status. There is growing evidence that bone morphogenetic protein (BMP) signaling is involved in vascular diseases, including atherosclerosis. Here, we evaluated in vitro the role of specific agonists/antagonists belonging to the BMP pathway on dedifferentiation of VSMC harvested during early stages of atherosclerosis. RESULTS: Comparing primary VSMC isolated from aortas of susceptible ApoE-/- animals fed 8 weeks of western diet with their littermate controls fed usual diet, we observed that recombinant BMP4 was able to reduce SM22-alpha and alpha actin gene expression indicating dedifferentiation was under way. Unexpectedly, treatment with recombinant Gremlin-1, a known BMP antagonist, also reduced 4-6.5 folds gene expression of SM22-alpha, alpha-actin and, calponin, exclusively in VSMC from ApoE-/- animals, independently on the diet consumed. CONCLUSION: Our data show that BMP4 is capable of modulating of SM22-alpha and alpha actin gene expression, indicative of cell dedifferentiation in VSMC. Additionally, we report for first time that Gremlin-1 acts independently of the BMP pathway and selectively on VSMC from susceptible animals, reducing the expression of all genes evaluated.

The Bone Marrow Microenvironment Mechanisms in Acute Myeloid Leukemia.

Bone marrow (BM) is a highly complex tissue that provides important regulatory signals to orchestrate hematopoiesis. Resident and transient cells occupy and interact with some well characterized niches to produce molecular and cellular mechanisms that interfere with differentiation, migration, survival, and proliferation in this microenvironment. The acute myeloid leukemia (AML), the most common and severe hematological neoplasm in adults, arises and develop in the BM. The osteoblastic, vascular, and reticular niches provide surface co-receptors, soluble factors, cytokines, and chemokines that mediate important functions on hematopoietic cells and leukemic blasts. There are some evidences of how AML modify the architecture and function of these three BM niches, but it has been still unclear how essential those modifications are to maintain AML development. Basic studies and clinical trials have been suggesting that disturbing specific cells and molecules into the BM niches might be able to impair leukemia competencies. Either through niche-specific molecule inhibition alone or in combination with more traditional drugs, the bone marrow microenvironment is currently considered the potential target for new strategies to treat AML patients. This review describes the cellular and molecular constitution of the BM niches under healthy and AML conditions, presenting this anatomical compartment by a new perspective: as a prospective target for current and next generation therapies.