It has recently been proposed that heart failure is a risk factor for Alzheimer′s disease. Decreased cerebral blood flow and neurohormonal activation due to heart failure may contribute to the dysfunction of the neurovascular unit and cause an energy crisis in neurons. This leads to the impaired clearance of amyloid beta and hyperphosphorylation of tau protein, resulting in the formation of amyloid beta plaques and neurofibrillary tangles. In this article, we will summarize the current understanding of the relationship between heart failure and Alzheimer′s disease based on epidemiological studies, brain imaging research, pathological findings and the use of animal models. The importance of atherosclerosis, myocardial infarction, atrial fibrillation, blood pressure and valve disease as well as the effect of relevant medications will be discussed.

Hepatocyte growth factor (HGF) has previously been reported to act as a hemangiogenic factor, as well as a mitogenic factor for a variety of tumor cells. Here, we demonstrate that HGF is a lymphangiogenic factor, which may contribute to lymphatic metastasis when overexpressed in tumors. In a mouse corneal lymphangiogenesis model, implantation of HGF induces sprouting and growth of new lymphatic vessel expressing the lymphatic vessel endothelial specific marker hyaluronan receptor-1 (Lyve-1). Unlike blood vessels, the Lyve-1–positive structures consist of blunt-ended vessels of large diameters that generally lack expression of CD31. The growth of HGF-induced lymphatic vessels can be partially blocked by a soluble VEGFR-3, suggesting that HGF may stimulate lymphatic vessel growth through an indirect mechanism. Consistent with this finding, the HGF receptor (c-Met) is only localized on corneal blood vessels but is absent on lymphatic vessels in a mouse corneal assay. In a transgenic mouse model that expresses HGF under the control of the whey acidic protein (WAP) gene promoter, transgenic females develop tumors in the mammary glands after several pregnancies. Interestingly, dilated Lyve-1–positive lymphatic vessels accumulate in the peritumoral area and occasionally penetrate into the tumor tissue. Our findings indicate that HGF may play a critical role in lymphangiogenesis and potentially contribute to lymphatic metastasis.

Metastases are commonly found in the lymphatic system. The molecular mechanism of lymphatic metastasis is, however, poorly understood. Here we report that vascular endothelial growth factor (VEGF)-A stimulated lymphangiogenesis in vivo and that overexpression of VEGF-A in murine T241 fibrosarcomas induced the growth of peritumoral lymphatic vessels, which occasionally penetrated into the tumor tissue. As a result of peritumoral lymphangiogenesis, metastases in lymph nodes of mice were detected. VEGF-A–overexpressing tumors contained high numbers of infiltrating inflammatory cells such as macrophages, which are known to express VEGF receptor (VEGFR)-1. It seemed that in the mouse cornea, VEGF-A stimulated lymphangiogenesis through a VEGF-C/-D/VEGFR-3–independent pathway as a VEGFR-3 antagonist selectively inhibited VEGF-C–induced, but not VEGF-A–induced, lymphangiogenesis. Our data show that VEGF-A contributes to lymphatic mestastasis. Thus, blockage of VEGF-A–induced lymphangiogenesis may provide a novel approach for prevention and treatment of lymphatic metastasis.

During breast cancer progression, transforming growth factor-beta (TGF-β) switches from acting as a growth inhibitor to become a major promoter of epithelial-mesenchymal transition (EMT), invasion and metastasis. However, the mechanisms involved in this switch are not clear. We found that loss of CCAAT-enhancer binding protein beta (C/EBPβ), a differentiation factor for the mammary epithelium, was associated with signs of EMT in triple-negative human breast cancer, and in invasive areas of mammary tumors in MMTV-PyMT mice. Using an established model of TGF-β-induced EMT in mouse mammary gland epithelial cells, we discovered that C/EBPβ was repressed during EMT by miR-155, an oncomiR in breast cancer. Depletion of C/EBPβ potentiated the TGF-β response towards EMT, and contributed to evasion of the growth inhibitory response to TGF-β. Furthermore, loss of C/EBPβ enhanced invasion and metastatic dissemination of the mouse mammary tumor cells to the lungs after subcutaneous injection into mice. The mechanism by which loss of C/EBPβ promoted the TGF-β response towards EMT, invasion and metastasis, was traced to a previously uncharacterized role of C/EBPβ as a transcriptional activator of genes encoding the epithelial junction proteins E-cadherin and coxsackie virus and adenovirus receptor. The results identify miR-155-mediated loss of C/EBPβ as a mechanism, which promotes breast cancer progression by shifting the TGF-β response from growth inhibition to EMT, invasion and metastasis.

The functional impact of amyloid peptides (Aβs) on the vascular system is less understood despite these pathologic peptides are substantially deposited in the brain vasculature of Alzheimer's patients. Here we show substantial accumulation of Aβs 40 and 42 in the brain arterioles of Alzheimer's patients and of transgenic Alzheimer's mice. Purified Aβs 1–40 and 1–42 exhibited vascular regression activity in the in vivo animal models and vessel density was reversely correlated with numbers and sizes of amyloid plaques in human patients. A significant high number of vascular cells underwent cellular apoptosis in the brain vasculature of Alzheimer's patients. VEGF significantly prevented Aβ-induced endothelial apoptosis in vitro. Neuronal expression of VEGF in transgenic mice restored memory behavior of Alzheimer's. These findings provide conceptual implication of improvement of vascular functions as a novel therapeutic approach for the treatment of Alzheimer's disease.