Final Report Summary - IMAGO (Imaging regulatory pathways of angiogenesis)
Homeostasis of multicellular tissues relies matching vascular supply and drain to the needs of the tissue. Multiple pathways are involved in detection, signaling and execution of the required steps involved in organization of blood and lymphatic vessels during embryonic development. Similar mechanisms are utilized for overcoming changes in tissue requirements also in adult tissues and in pathological processes. The goal of the IMAGO project was to reveal the dynamic forces that shape the blood vessels during angiogenesis.
The effects of interstitial pressure and hemodynamics on vascular remodeling were studied using genetic mouse models in which vascular permeability was modulated by changes in expression of Akt1. We showed that changes in Akt1 affect vessel diameter in the ovary and the placenta, they affect vessel growth in the long bones and affect the ratio of capillaries to major vessels in the heart. These effects have significant impact on tissue morphogenesis with potential impact to many diseases and therapeutic strategies. Those include the use of ovarian grafts for preservation of fertility in cancer survivors, complications in pregnancy including fetal implantation and intrauterine growth retardation and cardiovascular diseases including survival of heart function after myocardial infarction.
Our research yielded some un-expected results. For example, using arterial spin labeling, we were able to show distribution of perfusion areas within mice placenta that were perfused either from the ovarian artery or from the uterine artery. These patterns stand in contrast to the accepted evolutionary conserved anatomical description of a single uterine arterial loop generated by direct anastomosis of the two arteries. Such perfusion pattern can explain how multi-fetal pregnancies show position dependent effects based on the site of implantation, and remarkably also hemodynamic inter-fetal effects, in which the fetal phenotype is affected by the genotype of the adjacent fetus in the same litter.
We also showed that despite exposure to reduced vascular development, surprisingly Akt1 deficient mice show elevated resistance to myocardial infarction, apparently due to reduced adverse remodeling due to the preconditioning effects of development under genetically restricted vasculogenesis.
The extracellular matrix is a key factor in shaping angiogenesis. Our focus was on the role of hyaluronan, a negatively charged polysaccharide which controls adhesion, angiogenesis and metastasis in ovarian cancer.
Remodeling of the lymphatic vasculature was followed in tumors and during development. Our focus was on the microenvironmental control of lymphangiogenesis, and in that context we discovered the role of LEDGF in mediating hormonal and environmental stress induced lymphangiogenesis.
In order to follow vascular remodeling, we developed multi-modality and multi scale tools for imaging the regulation of vascular patterning. Whole body imaging methods applied optical, CT, ultrasound and MRI for non-invasive imaging of deep organs such as placenta and embryos, the heart and deep tumors. Microscopic morphometric and molecular information was derived from the macroscopic imaging data, using selective molecular imaging approaches and functional imaging tools with specific pharmacological models and image computation tools. Intravital two-photon microscopy was used for high resolution evaluation of vascular patterning using window chamber models. Reporter genes were developed for imaging apoptotic cell death and tracking recruitment of fibroblasts to tumors. These tools were applied across a wide range of systems for mapping vascular patterning in pathological and physiological angiogenesis including tumours, wound repair, the preovulatory ovarian follicle and foetal implantation sites.
The effects of interstitial pressure and hemodynamics on vascular remodeling were studied using genetic mouse models in which vascular permeability was modulated by changes in expression of Akt1. We showed that changes in Akt1 affect vessel diameter in the ovary and the placenta, they affect vessel growth in the long bones and affect the ratio of capillaries to major vessels in the heart. These effects have significant impact on tissue morphogenesis with potential impact to many diseases and therapeutic strategies. Those include the use of ovarian grafts for preservation of fertility in cancer survivors, complications in pregnancy including fetal implantation and intrauterine growth retardation and cardiovascular diseases including survival of heart function after myocardial infarction.
Our research yielded some un-expected results. For example, using arterial spin labeling, we were able to show distribution of perfusion areas within mice placenta that were perfused either from the ovarian artery or from the uterine artery. These patterns stand in contrast to the accepted evolutionary conserved anatomical description of a single uterine arterial loop generated by direct anastomosis of the two arteries. Such perfusion pattern can explain how multi-fetal pregnancies show position dependent effects based on the site of implantation, and remarkably also hemodynamic inter-fetal effects, in which the fetal phenotype is affected by the genotype of the adjacent fetus in the same litter.
We also showed that despite exposure to reduced vascular development, surprisingly Akt1 deficient mice show elevated resistance to myocardial infarction, apparently due to reduced adverse remodeling due to the preconditioning effects of development under genetically restricted vasculogenesis.
The extracellular matrix is a key factor in shaping angiogenesis. Our focus was on the role of hyaluronan, a negatively charged polysaccharide which controls adhesion, angiogenesis and metastasis in ovarian cancer.
Remodeling of the lymphatic vasculature was followed in tumors and during development. Our focus was on the microenvironmental control of lymphangiogenesis, and in that context we discovered the role of LEDGF in mediating hormonal and environmental stress induced lymphangiogenesis.
In order to follow vascular remodeling, we developed multi-modality and multi scale tools for imaging the regulation of vascular patterning. Whole body imaging methods applied optical, CT, ultrasound and MRI for non-invasive imaging of deep organs such as placenta and embryos, the heart and deep tumors. Microscopic morphometric and molecular information was derived from the macroscopic imaging data, using selective molecular imaging approaches and functional imaging tools with specific pharmacological models and image computation tools. Intravital two-photon microscopy was used for high resolution evaluation of vascular patterning using window chamber models. Reporter genes were developed for imaging apoptotic cell death and tracking recruitment of fibroblasts to tumors. These tools were applied across a wide range of systems for mapping vascular patterning in pathological and physiological angiogenesis including tumours, wound repair, the preovulatory ovarian follicle and foetal implantation sites.