Endothelial-epithelial communication in polycystic kidney disease: Role of vascular endothelial growth factor signalling

Abstract

Whereas targeting the cyst epithelium and its molecular machinery has been the prevailing clinical strategy for polycystic kidney disease, the endothelium, including blood vasculature and lymphatics, is emerging as an important player in this disorder. In this Review, we provide an overview of the structural and functional alterations to blood vasculature and lymphatic vessels in the polycystic kidney. We also discuss evidence for vascular endothelial growth factor signalling, otherwise critical for endothelial cell development and maintenance, as being a fundamental molecular pathway in polycystic kidney disease and a potential therapeutic target for modulating cyst expansion.

Modeling Neoplastic Growth in Renal Cell Carcinoma and Polycystic Kidney Disease

“…Vasculature appears abnormal in ADPKD, autosomal recessive (AR)PKD (reviewed in [49]), and cancer [50][51][52]. The peritubular reticular capillaries of the renal cortex regulate fluid balance through reabsorption of the glomerular filtrate.…”

“…The lymphatic capillaries that normally clear the interstitial fluid from around the organs are also remodeled, exhibit several malformations and decreased branching [58]. Compromised lymphatic function causes blood accumulation in the lymph sacs and contributes to early lethality of the Pkd1 −/− , Pkd1 nl/nl , Pkd1 RC/RC , and Pkd2 −/− mice [49,57,59,60]. Reminiscent of tumor growth, cyst expansion also requires a shift in the vasculature to provide metabolites to support angiogenesis, through a temporary repair mechanism generating new vessels from existing vasculature to supply blood to the repaired tissue [61].…”

“…The peritubular reticular capillaries of the renal cortex regulate fluid balance through reabsorption of the glomerular filtrate. In ADPKD, the renal blood vessels are remodeled, which is thought to contribute to disease progression [49,53]. In both ADPKD patients and the Pkd1 nl/nl mice, the peritubular capillaries become spiral-shaped, convoluted, and dilated [54][55][56].…”

“…A primary growth factor promoting angiogenesis is vascular endothelial growth factor (VEGF)-A, which binds to receptor VEGFR-2 to promote blood endothelial cell proliferation, differentiation, migration, and survival [62]. Expressed in cortical tubules and large cysts, VEGF-A could promote cyst expansion through increased angiogenesis [49,63]. In lymphatic endothelial cells, activation of another growth factor, VEGF-C, and its receptor VEGFR-3, also promotes cell proliferation, differentiation, migration, and survival [60], but the specifics are not fully understood [49].…”

“…Expressed in cortical tubules and large cysts, VEGF-A could promote cyst expansion through increased angiogenesis [49,63]. In lymphatic endothelial cells, activation of another growth factor, VEGF-C, and its receptor VEGFR-3, also promotes cell proliferation, differentiation, migration, and survival [60], but the specifics are not fully understood [49]. Current knowledge suggests that VEGF-C activation may ameliorate PKD by increasing lymphatic vessels, leading to the clearance of excess fluids and inflammatory cells from the renal interstitial space [56].…”