Molecular regulation of angiogenesis and lymphangiogenesis

Blood vessels and lymphatic vessels form extensive networks that are essential for the transport of fluids, gases, macromolecules and cells within the large and complex bodies of vertebrates. Both of these vascular structures are lined with endothelial cells that integrate functionally into different organs, acquire tissue-specific specialization and retain plasticity; thereby, they permit growth during tissue repair or in disease settings. The angiogenic growth of blood vessels and lymphatic vessels coordinates several biological processes such as cell proliferation, guided migration, differentiation and cell-cell communication.     

Molecular mechanisms of lymphangiogenesis in development and cancer

The lymphatic system, also named the second vascular system, plays a critical role in tissue homeostasis and immunosurveillance. The past two decades of intensive research have led to the identification and detailed understanding of many molecular players and mechanisms regulating the formation of the lymphatic vasculature during embryonic development. Furthermore, clinical and experimental data clearly demonstrate that the formation of new lymphatic vessels by sprouting lymphangiogenesis from pre-existing lymphatic vessels, or by the de novo formation of lymphatic capillaries also occurs in various pathological conditions, such as cancer and organ transplant rejection, while lymphangiogenesis is non-functional in primary edema. In cancer, lymphatic vessels are one major gateway for invasive tumor cells to leave the primary tumor site and to establish distant organ metastasis. Therefore, the specific targeting of the lymphatic vasculature at the tumor site could be a promising approach to prevent metastasis formation.     

Molecular regulation of lymphangiogenesis and targets for tissue oedema.

New insight has recently been obtained into the molecular mechanisms regulating the function of lymphatic endothelial cells. Vascular endothelial growth factors-C and -D have been shown to stimulate lymphangiogenesis, and their receptor VEGFR-3 has been linked to human hereditary lymphoedema, although there is evidence that other genes are also involved. These data suggest that it may become possible to stimulate lymphatic growth and function and to treat tissue oedema involved in many diseases.     

肿瘤淋巴管生成

相对于肿瘤的血管生成（angiogenesis）而言,肿瘤中的淋巴管生成（lymphangiogenesis）是一个长期受到争议和忽视的问题。但近来的实验证明：肿瘤细胞可以通过表达淋巴管生成的调控因子VEGF-C和VEGF-D诱导淋巴管生成,并且促进肿瘤细胞的淋巴道转移。这些发现使得淋巴管生成开始成为研究肿瘤淋巴道转移的焦点,并有可能成为治疗肿瘤淋巴道转移的靶点。     

Inflammatory triggers of lymphangiogenesis

Inflammation is the common denominator to the postnatal events that overlap with lymphatic vessel growth, or lymphangiogenesis. Undoubtedly, inflammation and accompanying fluid overload are cardinal factors in wound healing, lymphedema, the pathogenesis of some forms of lymphangiomatosis, and solid tumor lymphangiogenesis. The assertion that inflammation actually triggers lymphangiogenesis lies in the evidence set forth below that inflammation is the usual precursor to tissue repair and regeneration. Moreover, the panel of pro-inflammatory and anti-inflammatory molecules that orchestrates the inflammatory response abounds with cytokines and chemokines that foster survival, migration, and proliferation of lymphatic endothelial cells. Finally, both interstitial fluid overload and increased demand for removal of leukocytes can benefit from lymphangiogenesis, although the mechanisms controlling the exit of leukocytes from tissues via the lymphatics are practically unknown. The pertinent question actually is how and why inflammation presents with formation of new lymph vessels in liver fibrosis but not in rheumatoid arthritis. One possible explanation is that organ-specific histological and functional properties of the lymphatic endothelium gauge their response to death, survival, and proliferative factors. Alternatively, the decision to remain quiescent, proliferate or regress resides within the stroma microenvironment.     

Molecular control of oogenesis

Oogenesis is a complex process regulated by a vast number of intra- and extra-ovarian factors. Oogonia, which originate from primordial germ cells, proliferate by mitosis and form primary oocytes that arrest at the prophase stage of the first meiotic division until they are fully-grown. Within primary oocytes, synthesis and accumulation of RNAs and proteins throughout oogenesis are essential for oocyte growth and maturation; and moreover, crucial for developing into a viable embryo after fertilization. Oocyte meiotic and developmental competence is gained in a gradual and sequential manner during folliculogenesis and is related to the fact that the oocyte grows in interaction with its companion somatic cells. Communication between oocyte and its surrounding granulosa cells is vital, both for oocyte development and for granulosa cells differentiation. Oocytes depend on differentiated cumulus cells, which provide them with nutrients and regulatory signals needed to promote oocyte nuclear and cytoplasmic maturation and consequently the acquisition of developmental competence.The purpose of this article is to summarize recent knowledge on the molecular aspects of oogenesis and oocyte maturation, and the crucial role of cumulus–cell interactions, highlighting the valuable contribution of experimental evidences obtained in animal models. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.     

Mouse corneal lymphangiogenesis model

This protocol describes a powerful in vivo method to quantitatively study the formation of new lymphatic vessels in the avascular cornea without interference of pre-existing lymphatics. Implantation of 100 ng of lymphangiogenic factors such as vascular endothelial growth factor (VEGF)-A, VEGF-C or fibroblast growth factor-2, together with slow-release polymers, into a surgically created micropocket in the mouse cornea elicits a robust lymphangiogenic response. Newly formed lymphatic vessels are detected by immunohistochemical staining of the flattened corneal tissue with lymphatic endothelial-specific markers such as lymphatic vessel endothelial hyaluronan receptor-1; less-specific markers such as vascular endothelial growth factor receptor 3 may also be used. Lymphatic vessel growth in relation to hemangiogenesis can be readily detected starting at day 5 or 6 after pellet implantation and persists for ～14 d. This protocol offers a unique opportunity to study the mechanisms underlying lymphatic vessel formation, remodeling and function.     

Molecular control of neuronal migration

Our understanding of neuronal migration has been advanced by multidisciplinary approaches. At the cellular level, tangential and radial modes of neuronal migration contribute to different populations of neurons and have differential dependence on glial cells. At the molecular level, extracellular guidance cues have been identified and intracellular signal transduction pathways are beginning to be revealed. Interestingly, mechanisms guiding axon projection and neuronal migration appear to be conserved with those for chemotactic leukocytes.     

Molecular control of neutrophil apoptosis

Human neutrophils constitutively undergo apoptosis and this process is critical for the resolution of inflammation. Whilst neutrophil apoptosis can be modulated by a wide variety of agents including GM-CSF, LPS and TNF-alpha, the molecular mechanisms underlying neutrophil death and survival remain largely undefined. Recent studies have shown the involvement of members of the Bcl-2 protein family (especially Mcl-1 and A1) and caspases in the regulation and execution of neutrophil apoptosis. Cell surface receptors and protein kinases, particularly mitogen-activated protein kinases, also play critical roles in transducing the signals that result in neutrophil apoptosis or extended survival. This review summarises current knowledge on the molecular mechanisms and components of neutrophil apoptosis.     

Molecular biology of weed control

The vast commercial effort to utilize chemical and molecular tools to solve weed control problems has had a major impact on the basic biological sciences as well as benefits to agriculture, and the first generation of transgenic products has been successful, while somewhat crude. More sophisticated products are envisaged and expected. Biotechnologically-derived herbicide-resistant crops have been a considerable benefit, yet in some cases there is a risk that the same useful transgenes may introgress into related weeds, specifically the weeds that are hardest to control without such transgenic crops. Biotechnology can also be used to mitigate the risks. Molecular tools should be considered for weed control without the use of, or with less chemicals, whether by enhancing crop competitiveness with weeds for light, nutrients and water, or via allelochemicals. Biocontrol agents may become more effective as well as more safe when rendered hypervirulent yet non-spreading by biotechnology. There might be ways to disperse deleterious transposons throughout weed populations, obviating the need to modify the crops. This revised version was published online in August 2006 with corrections to the Cover Date.     

Molecular control of angiopoietin signalling

The angiopoietins act through the endothelial receptor tyrosine kinase Tie2 to regulate vessel maturation in angiogenesis and control quiescence and stability of established vessels. The activating ligand, Ang1 (angiopoietin-1), is constitutively expressed by perivascular cells, and the ability of endothelial cells to respond to the ligand is controlled at the level of the Ang1 receptor. This receptor interacts with the related protein Tie1 on the cell surface, and Tie1 inhibits Ang1 signalling through Tie2. The responsiveness of endothelium to Ang1 is determined by the relative levels of Tie2 and the inhibitory co-receptor Tie1 in the cells. Tie1 undergoes regulated ectodomain cleavage which is stimulated by a range of factors including VEGF (vascular endothelial growth factor), inflammatory cytokines and changes in shear stress. Ectodomain cleavage of Tie1 relieves inhibition of Tie2 and enhances Ang1 signalling. This mechanism regulates Ang1 signalling without requiring changes in the level of the ligand and allows Ang1 signalling to be co-ordinated with other signals in the cellular environment. Regulation of signalling at the level of receptor responsiveness may be an important adaptation in systems in which an activating ligand is normally present in excess or where the ligand provides a constitutive maintenance signal.     

Molecular control of facial morphology

We present a developmental perspective on the concept of phylotypic and phenotypic stages of craniofacial development. Within orders of avians and mammals, a phylotypic period exists when the morphology of the facial prominences is minimally divergent. We postulate that species-specific facial variations arise as a result of subtle shifts in the timing and the duration of molecular pathway activity (e.g., heterochrony), and present evidence demonstrating a critical role for Wnt and FGF signaling in this process. The same molecular pathways that shape the vertebrate face are also implicated in craniofacial deformities, indicating that comparisons between and among animal species may represent a novel method for the identification of human craniofacial disease genes.