Decreased interstitial flow (IF) in secondary lymphedema is coincident with poor physiological lymphatic regeneration. However, both the existence and direction of causality between IF and lymphangiogenesis remain unclear. This is primarily because the role of IF and its importance relative to the action of the prolymphangiogenic growth factor vascular endothelial growth factor (VEGF)-C (which signals primarily through its receptor VEGFR-3) are poorly understood. To clarify this, we explored the cooperative roles of VEGFR-3 and IF in a mouse model of lymphangiogenesis in regenerating skin. Specifically, a region of lymphangiogenesis was created by substituting a portion of mouse tail skin with a collagen gel within which lymphatic capillaries completely regenerate over a period of 60 days. The relative importance of IF and VEGF-C signaling were evaluated by either inhibiting VEGFR-3 signaling with antagonistic antibodies or by reducing IF. In some cases, VEGF-C signaling was then increased with exogenous protein. To clarify the role of IF, the distribution of endogenous matrix metalloproteinases (MMPs) and VEGF-C within the regenerating region was determined. It was found that inhibition of either VEGFR-3 or IF suppressed endogenous lymphangiogenesis. Reduction of IF was found to decrease lymphatic migration and transport of endogenous MMP and VEGF-C through the regenerating region. Therapeutic VEGF-C administration restored lymphangiogenesis following inhibition of VEGFR-3 but did not increase lymphangiogenesis following inhibition of IF. These results identify IF as an important regulator of the pro-lymphangiogenic action of VEGF-C.

Jeremy Goldman

Kelly A. Conley

Alisha Raehl

Dona M. Bondy

Bronislaw Pytowski

Melody A. Swartz

Joseph M. Rutkowski

David B. Jaroch

Emily L. Ongstad

AJP Heart and Circulatory Physiology

美国生理学杂志-心脏和循环生理学发表关于心脏、脉管系统和淋巴系统生理学的原始调查、评论和观点。这些文章包括从完整和整合的动物和器官功能到细胞、亚细胞和分子水平的各个组织水平的心血管功能的实验和理论研究。该杂志包含了对这些功能及其控制系统的新描述，以及它们在生物化学、生物物理学、遗传学和细胞生物学中的基础。优先考虑提供重要的新机械生理学见解的研究，这些见解可以确定正常和异常心脏和循环的表现。

The American Journal of Physiology - Heart and Circulatory Physiology publishes original investigations, reviews, and perspectives on the physiology of the heart, vascular system, and lymphatic system. These articles cover experimental and theoretical studies of cardiovascular function at various levels, from whole and integrated animal and organ functions to cellular, subcellular, and molecular levels. The journal includes new descriptions of these functions and their control systems, as well as their foundations in biochemistry, biophysics, genetics, and cell biology. Research providing significant new insights into mechanical physiology that can elucidate the performance of normal and abnormal heart and circulatory functions is prioritized.

《American Journal of Physiology - Heart and Circulatory Physiology》发表关于心脏、血管系统和淋巴系统生理学的原创研究、评论和观点。这些文章涵盖了从整体和综合的动物及器官功能到细胞、亚细胞和分子水平的心血管功能的实验和理论研究。该杂志包含对这些功能及其控制系统的新描述，以及它们在生物化学、生物物理学、遗传学和细胞生物学中的基础。优先考虑提供重要的新机械生理学见解的研究，这些见解能够阐明正常和异常心脏及循环的表现。

American Journal of Physiology - Heart and Circulatory Physiology

Regulation of lymphatic capillary regeneration by interstitial flow in skin

IF is identified as an important regulator of the pro-lymphangiogenic action of VEGF-C in a mouse model of lymphangiogenesis in regenerating skin.

Category	Quartile
医学	2
医学, 生理学	2
医学, 心脏和心血管系统	3
医学, 外周血管病	3

Regulation of lymphatic capillary regeneration by interstitial flow in skin

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