The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease.

Ageing is the main risk factor for the development of cardiovascular diseases. A central mechanism by which ageing promotes vascular pathologies is compromising endothelial health. The age-related attenuation of endothelium-dependent dilator responses (endothelial dysfunction) associated with impairment of angiogenic processes and the subsequent pathological remodelling of the microcirculation contribute to compromised tissue perfusion and exacerbate functional decline in older individuals. This Review focuses on cellular, molecular, and functional changes that occur in the endothelium during ageing. We explore the links between oxidative and nitrative stress and the conserved molecular pathways affecting endothelial dysfunction and impaired angiogenesis during ageing. We also speculate on how these pathological processes could be therapeutically targeted. An improved understanding of endothelial biology in older patients is crucial for all cardiologists because maintenance of a competently functioning endothelium is critical for adequate tissue perfusion and long-term cardiac health.

Angiogenesis and lymphangiogenesis often occur in response to tissue injury or in the presence of pathology (e.g. cancer), and it is these types of environments in which macrophages are activated and increased in number. Moreover, the blood vascular microcirculation and the lymphatic circulation serve as the conduits for entry and exit for monocyte-derived macrophages in nearly every tissue and organ. Macrophages both affect and are affected by the vessels through which they travel. Therefore, it is not surprising that examination of macrophage behaviors in both angiogenesis and lymphangiogenesis has yielded interesting observations that suggest macrophages may be key regulators of these complex growth and remodeling processes. In this review, we will take a closer look at macrophages through the lens of angiogenesis and lymphangiogenesis, examining how their dynamic behaviors may regulate vessel sprouting and function. We present macrophages as a cellular link that spatially and temporally connects angiogenesis with lymphangiogenesis, in both physiological growth and in pathological adaptations, such as tumorigenesis. As such, attempts to therapeutically target macrophages in order to affect these processes may be particularly effective, and studying macrophages in both settings will accelerate the field’s understanding of this important cell type in health and disease.

Therapies aimed at manipulating the microcirculation require the ability to control angiogenesis, defined as the sprouting of new capillaries from existing vessels. Blocking angiogenesis would be beneficial in many pathologies (e.g. cancer, retinopathies and rheumatoid arthritis). In others (e.g. myocardial infarction, stroke and hypertension), promoting angiogenesis would be desirable. We know that vascular pericytes elongate around endothelial cells (ECs) and are functionally associated with regulating vessel stabilization, vessel diameter and EC proliferation. During angiogenesis, bidirectional pericyte-EC signaling is critical for capillary sprout formation. Observations of pericytes leading capillary sprouts also implicate their role in EC guidance. As such, pericytes have recently emerged as a therapeutic target to promote or inhibit angiogenesis. Advancing our basic understanding of pericytes and developing pericyte-related therapies are challenged, like in many other fields, by questions regarding cell identity. This review article discusses what we know about pericyte phenotypes and the opportunity to advance our understanding by defining the specific pericyte cell populations involved in capillary sprouting.

Developing therapies aimed at manipulating microvascular remodeling requires a better understanding of angiogenesis and how angiogenesis relates to other network remodeling processes, such as lymphangiogenesis and neurogenesis. The objective of this study was to develop an angiogenesis model that enables probing of multicellular and multisystem interactions at the molecular level across an intact adult microvascular network. Adult male Wistar rat mesenteric windows were aseptically harvested and cultured in serum-free minimum essential media. Viability/cytotoxicity analysis revealed that cells remain alive for at least 7 days. Immunohistochemical labeling at 3 days for platelet endothelial cell adhesion molecule (PECAM), neuron-glial antigen 2 (NG2), lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), and class III β-tubulin identified endothelial cells, pericytes, lymphatics, and nerves, respectively. Media supplemented with bFGF or VEGF induced an increase in endothelial cell sprouting off existing vessels. Endothelial cell sprouting in both growth factor groups was inhibited by targeting pericytes with NG2 functional blocking antibody. VEGF caused an increase in the number of lymphatic/blood endothelial cell connections compared with media alone or bFGF groups. Finally, the comparison of the same network before and after angiogenesis stimulated by the supplement of media with 20% serum identified the ability of disconnected endothelial segments to reconnect to nearby vessels. The results establish a novel in situ angiogenesis model for investigating the location of capillary sprouting within an intact network, the role of pericytes, lymphatic/blood endothelial cell interactions, and the fate of specific endothelial cell segments. The rat mesentery culture system offers a unique tool for understanding the complex dynamics associated with angiogenesis in an intact adult tissue.