Aspelund et al. discover the presence of a lymphatic vessel network in the dura mater of the mouse brain and show that these dural lymphatic vessels are important for the clearance of macromolecules from the brain.
The interstitium describes the fluid, proteins, solutes, and the extracellular matrix (ECM) that comprise the cellular microenvironment in tissues. Its alterations are fundamental to changes in cell function in inflammation, pathogenesis, and cancer. Interstitial fluid (IF) is created by transcapillary filtration and cleared by lymphatic vessels. Herein we discuss the biophysical, biomechanical, and functional implications of IF in normal and pathological tissue states from both fluid balance and cell function perspectives. We also discuss analysis methods to access IF, which enables quantification of the cellular microenvironment; such methods have demonstrated, for example, that there can be dramatic gradients from tissue to plasma during inflammation and that tumor IF is hypoxic and acidic compared with subcutaneous IF and plasma. Accumulated recent data show that IF and its convection through the interstitium and delivery to the lymph nodes have many and diverse biological effects, including in ECM reorganization, cell migration, and capillary morphogenesis as well as in immunity and peripheral tolerance. This review integrates the biophysical, biomechanical, and biological aspects of interstitial and lymph fluid and its transport in tissue physiology, pathophysiology, and immune regulation.
The skin interstitium sequesters excess Na + and Cl -in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl -accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na + , Cl -, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function.
Platelet-derived growth factor-D (PDGF-D IntroductionPlatelet-derived growth factor (PDGF) is a mitogen for various cell types, including fibroblasts and smooth muscle cells. Although originally purified from human platelets, 1 current data indicate that several different cell types can produce PDGF in vitro and in vivo. 2 Until recently, the PDGF family of growth factors was composed of PDGF-A and PDGF-B chain homodimers and heterodimers. Recently, however, 2 novel homologous genes were isolated, PDGF-C 3 and PDGF-D. 4-6 PDGF-C and PDGF-D form disulfide-bonded homodimers, but they do not appear to heterodimerize with PDGF-A or PDGF-B chains, and they differ from the latter by having an N-terminal CUB-domain that is proteolytically cleaved before receptor binding. [3][4][5] PDGFs bind to and activate 2 structurally related protein tyrosine kinase receptors, PDGF receptor-␣ and PDGF receptor-. According to published data, the ␣-receptor binds PDGF-AA, PDGF-BB, PDGF-AB, and PDGF-CC, whereas the -receptor binds PDGF-BB and PDGF-DD. [2][3][4] Although the exact biologic functions of PDGF-D are unknown, it has been shown to stimulate tumor growth and angiogenesis, 7-9 and it is implicated in glomerulonephritis. 10 Considerable interest focuses on the potential role of PDGF-D in wound healing. Reepithelialization, extracellular matrix deposition, and angiogenesis are all part of the wound healing process, and PDGFs are involved in various stages of this process (for a review, see Martin 11 ).Although most of the PDGF-B in wounds is produced by cells of hematopoietic origin, 12 wound healing occurs normally in mice that undergo transplantation with bone marrow derived from pdgfb null mice. 13 This result suggests a redundancy of PDGF-B-like growth factors. PDGF-D could perhaps provide a redundant function because it also binds to and activates one of the receptors for PDGF-B.Here we have addressed the effects of PDGF-D overexpression in normal skin and muscle and its effects on wound healing. We overexpressed the human PDGF-D cDNA under the keratin 14 (K14) promoter in the basal skin keratinocytes of transgenic mice. Because this promoter is strongly up-regulated during the woundhealing process, abundant PDGF-D is delivered to the wounds. 14 Furthermore, we cloned full-length PDGF-D and the activated growth factor domain into an adeno-associated virus (AAV) vector, overexpressed it alone or in combination with a known angiogenic factor, vascular endothelial growth factor-E (VEGF-E), and examined its effects on the generated blood vessels. Materials and methods Generation and analysis of K14-PDGF-D transgenic miceHuman PDGF-D cDNA (base pair [bp] 176-1285; GenBank sequence number AF336376) was inserted into the BamHI site of the K14 promoter expression vector 15 ( Figure 1A). The resultant construct was digested with EcoRI and SphI, and the expression cassette was purified. A 5-ng/mL For personal use only. on June 19, 2019. by guest www.bloodjournal.org From solution of the DNA was injected into fertilized eggs of t...
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