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Geert Carmeliet

Publications and source records attributed to Geert Carmeliet.

24 records · Page 2Linked to original sources
PubMed2003

Disorders of calcium homeostasis.

To ensure a multitude of essential cellular functions, the extracellular concentration of calcium is maintained within a narrow physiological range. This depends on integrated regulation of calcium fluxes with respect to the intestine, kidneys and bone. The precise regulation of serum calcium is controlled by calcium itself, through a calcium receptor and several hormones, the most important of which are parathyroid hormone and 1,25(OH)(2) vitamin D. This balance can be disturbed by mutations in the calcium-sensing receptor, inappropriately high or low levels of parathyroid hormone, resistance to parathyroid hormone effects, insufficient intake or production of 1,25(OH)(2) vitamin D and inactivation of the vitamin D receptor. Mineral homeostasis is moreover influenced by many other systemic factors (e.g. sex steroid, thyroid and glucocorticoid hormones) or humoral factors (e.g. cytokines and growth factors). A specific example is the major abnormalities of mineral homeostasis in case of malignancy by excessive production of parathyroid hormone-related peptide resulting in hypercalcaemia. Several new drugs have been developed based on factors in this axis, including calcimimetics, calcilytics, vitamin D analogues and parathyroid hormone-related peptide inhibitors.

Animals↗
PubMed2002

Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1.

The therapeutic potential of placental growth factor (PlGF) and its receptor Flt1 in angiogenesis is poorly understood. Here, we report that PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to vascular endothelial growth factor (VEGF). An antibody against Flt1 suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in autoimmune arthritis. Anti-Flt1 also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not attributable to reduced plaque neovascularization. Inhibition of VEGF receptor Flk1 did not affect arthritis or atherosclerosis, indicating that inhibition of Flk1-driven angiogenesis alone was not sufficient to halt disease progression. The anti-inflammatory effects of anti-Flt1 were attributable to reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; impaired infiltration of Flt1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells. Thus, PlGF and Flt1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.

Animals↗
PubMed2002

Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188.

Vascular endothelial growth factor (VEGF)-mediated angiogenesis is an important part of bone formation. To clarify the role of VEGF isoforms in endochondral bone formation, we examined long bone development in mice expressing exclusively the VEGF120 isoform (VEGF120/120 mice). Neonatal VEGF120/120 long bones showed a completely disturbed vascular pattern, concomitant with a 35% decrease in trabecular bone volume, reduced bone growth and a 34% enlargement of the hypertrophic chondrocyte zone of the growth plate. Surprisingly, embryonic hindlimbs at a stage preceding capillary invasion exhibited a delay in bone collar formation and hypertrophic cartilage calcification. Expression levels of marker genes of osteoblast and hypertrophic chondrocyte differentiation were significantly decreased in VEGF120/120 bones. Furthermore, inhibition of all VEGF isoforms in cultures of embryonic cartilaginous metatarsals, through the administration of a soluble receptor chimeric protein (mFlt-1/Fc), retarded the onset and progression of ossification, suggesting that osteoblast and/or hypertrophic chondrocyte development were impaired. The initial invasion by osteoclasts and endothelial cells into VEGF120/120 bones was retarded, associated with decreased expression of matrix metalloproteinase-9. Our findings indicate that expression of VEGF164 and/or VEGF188 is important for normal endochondral bone development, not only to mediate bone vascularization but also to allow normal differentiation of hypertrophic chondrocytes, osteoblasts, endothelial cells and osteoclasts.

Animals↗
PubMed2002

Vascular progenitors: from biology to treatment.

The identification of endothelial progenitor cells (EPCs) in the adult human has forced us to reconsider how new blood vessels grow in physiological and pathological conditions in the adult human. An important question in angiogenesis research is to what extent these progenitors functionally contribute to revascularization of ischemic tissues and and to what extent they can be used for therapeutic angiogenic cell transplantation. Even more challenging is the concept that hematopoietic and other bone-marrow-derived stem cells might be recruited in the context of ischemia to induce neovessel formation. This review discusses some of the recent insights and outstanding questions on EPCs, both from a biological and therapeutic perspective.

Adult↗
PubMed2002

The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent.

Plasminogen activator inhibitor 1 (PAI-1) is believed to control proteolytic activity and cell migration during angiogenesis. We previously demonstrated in vivo that this inhibitor is necessary for optimal tumor invasion and vascularization. We also showed that PAI-1 angiogenic activity is associated with its control of plasminogen activation but not with the regulation of cell-matrix interaction. To dissect the role of the various components of the plasminogen activation system during angiogenesis, we have adapted the aortic ring assay to use vessels from gene-inactivated mice. The single deficiency of tPA, uPA, or uPAR, as well as combined deficiencies of uPA and tPA, did not dramatically affect microvessel formation. Deficiency of plasminogen delayed microvessel outgrowth. Lack of PAI-1 completely abolished angiogenesis, demonstrating its importance in the control of plasmin-mediated proteolysis. Microvessel outgrowth from PAI-1-/- aortic rings could be restored by adding exogenous PAI-1 (wild-type serum or purified recombinant PAI-1). Addition of recombinant PAI-1 led to a bell-shaped angiogenic response clearly showing that PAI-1 is proangiogenic at physiological concentrations and antiangiogenic at higher levels. Using specific PAI-1 mutants, we could demonstrate that PAI-1 promotes angiogenesis at physiological (nanomolar) concentrations through its antiproteolytic activity rather than by interacting with vitronectin.

Animals↗