Matthias Friedrich

Bio: Matthias Friedrich is an academic researcher from Cornell University. The author has contributed to research in topics: Kinase insert domain receptor & Angiogenesis. The author has an hindex of 4, co-authored 4 publications receiving 2335 citations.

Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors

Abstract: The neurotrophin brain-derived neurotrophic factor (BDNF) is required for the maintenance of cardiac vessel wall stability during embryonic development through direct angiogenic actions on endothelial cells expressing the tropomysin receptor kinase B (TrkB). However, the role of BDNF and a related neurotrophin ligand, neurotrophin-4 (NT-4), in the regulation of revascularization of the adult tissues is unknown. To study the potential angiogenic capacity of BDNF in mediating the neovascularization of ischemic and non-ischemic adult mouse tissues, we utilized a hindlimb ischemia and a subcutaneous Matrigel model. Recruitment of endothelial cells and promotion of channel formation within the Matrigel plug by BDNF and NT-4 was comparable to that induced by VEGF-A. The introduction of BDNF into non-ischemic ears or ischemic limbs induced neoangiogenesis, with a 2-fold increase in the capillary density. Remarkably, treatment with BDNF progressively increased blood flow in the ischemic limb over 21 days, similar to treatment with VEGF-A. The mechanism by which BDNF enhances capillary formation is mediated in part through local activation of the TrkB receptor and also by recruitment of Sca-1 + CD11b + pro-angiogenic hematopoietic cells. BDNF induces a potent direct chemokinetic action on subsets of marrow-derived Sca-1 + hematopoietic cells co-expressing TrkB. These studies suggest that local regional delivery of BDNF may provide a novel mechanism for inducing neoangiogenesis through both direct actions on local TrkB-expressing endothelial cells in skeletal muscle and recruitment of specific subsets of TrkB + bone marrow–derived hematopoietic cells to provide peri-endothelial support for the newly formed vessels.

Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity.

Abstract: Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity

Angiogenesis: vascular remodeling of the extracellular matrix involves metalloproteinases.

Abstract: Endothelial cell invasion is an essential event during angiogenesis (the formation of new blood vessels). This process involves the degradation of the extracellular matrix, the basement membrane, and interstitial stroma, and is governed by the activation of matrix metalloproteinases. However, the contribution of matrix metalloproteinases in angiogenesis is much more complicated. Tumor growth above a certain size is dependent on new vessels. A number of studies have demonstrated that treating tumors with matrix metalloproteinase inhibitors results in tumor reduction and a decrease in tumor angiogenesis. Matrix metalloproteinases as sole matrix eaters or degraders is a matter of the past. Not only tumor cells but more importantly bystander cells such as stromal cells produce matrix metalloproteinases. Matrix metalloproteinases therefore are also part of the pathologic microenvironment in different diseases. This enzymatic microenvironment dictates the endothelial cell fate, the angiogenic switch, and finally angiogenesis. During recent years, the role of matrix metalloproteinases has expanded, and their function as modulators of biologically active signaling molecules has drawn much attention. Depending on their substrate (growth factors or their receptors, extracellular matrix components, and angiogenic factors), matrix metalloproteinase activation results in the generation of proangiogenic or antiangiogenic factors. These data challenge the old concept that matrix metalloproteinases are simply proangiogenic. The knowledge of the local enzymatic profile and what, where, and how matrix metalloproteinases are involved in angiogenesis of tumors or other diseases will help design future therapeutic strategies better reflecting the complexity of the underlying biologic process of angiogenesis.

Molecular mechanisms and clinical applications of angiogenesis

Abstract: Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

Abstract: The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.