BMP6 as a Target for Pro-Angiogenic Therapies

Today's research materials are focused on the fine details of angiogenesis, the formation of new blood vessels, and point to BMP6 as a potential target to increase or diminish that process. Angiogenesis is very well studied by the cancer community, in the context of how tumors subvert tissue signaling to support themselves via the generation of blood vessel networks. Angiogenesis is perhaps an underappreciated topic in the study of aging, however, and particularly with regard to the treatment of aging as a medical condition. There is a good argument to be made that the observed loss of capillary density in older individuals is an important aspect of degenerative aging, a downstream consequence of poorly understood chains of cause and effect, that in turn leads to disruption of blood pressure maintenance and feedback systems, and diminished delivery of nutrients to tissues throughout the body.

A few fairly blunt approaches to boosting angiogenesis have been demonstrated in mice. This is largely in the context of cardiovascular disease, however, trying to encourage the creation of additional larger blood vessels that can bypass areas of damage. Growing such additional blood vessels prior to a cardiovascular event would obviously be preferable, and this is a plausible goal for the future of medicine. One strategy is to mobilize hematopoietic and endothelial cells from the bone marrow, using much the same class of treatment that is employed to collect donor cells for hematopoietic stem cell transplantation. These cells are involved in angiogenesis, and when the vasculature is flooded with them, more angiogenesis takes place.

Effects on capillary density have yet to be assessed, unfortunately. This is a part of the field that merits greater attention. For example, an intriguing study showed that mouse life span is extended by a related class of hematopoietic cell mobilizing drug. The mechanism of action was left undetermined, however. It could as well be improved immune function via increased hematopoietic generation of immune cells as improved vascular function via restoration of blood vessel density. This uncertainty following a result in which aging is in some way turned back is exactly why more research is needed on this topic.

New insight into neovessel formation shows promise in future treatment of cardiovascular diseases

Bone morphogenetic proteins, BMPs, are growth factors originally discovered as regulators in bone formation. Later on, their regulatory role on the development and maintenance of a wide range of tissues has become apparent. BMPs have a vital role in the development of the cardiovascular system. In addition, BMPs have been shown to regulate blood vessel formation but their exact mechanisms are unknown. Crosstalk of BMP-signalling with a well-known blood vessel formation regulator, VEGF, and its downstream effectors is poorly understood.

The new study now shows that VEGF gene transfer or oxygen deprivation of the tissue induce the expression of BMPs. Bone morphogenetic factor 6 (BMP6) ligand was further demonstrated, for the first time, to regulate blood vessel formation. BMP6 was shown to act in endothelial cells via VEGFR2 and Hippo signalling pathways by inducing nuclear localization of Hippo signalling pathway mediator TAZ. The findings from this research improve our understanding of multifactorial communication of cell signalling pathways in blood vessel formation. The discoveries related to BMP6 and Hippo signalling can be used in the development of novel treatments for cardiovascular diseases.

BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF

BMP family members are important regulators of both vascular homeostasis and angiogenesis. Synergistic effect of VEGF and BMPs on vasculature have been previously detected in bone formation but their role in angiogenesis, particularly crosstalk with VEGFR2 signaling has remained elusive. Our data demonstrate that BMPs are widely expressed in endothelium of various tissues in hypoxia or normoxia and after VEGF-induced angiogenesis, and that BMP2 and BMP6 regulate VEGFR and Notch signaling. BMP6 was further demonstrated to induce neovessel formation in vivo. This is the first comprehensive data on BMPs in hypoxia, and in angiogenesis in various animal models.

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