miR-126 Regulates Angiogenic Signaling and Vascular Integrity

Abstract

Summary Precise regulation of the formation, maintenance, and remodeling of the vasculature is required for normal development, tissue response to injury, and tumor progression. How specific microRNAs intersect with and modulate angiogenic signaling cascades is unknown. Here we identified microRNAs that were enriched in endothelial cells derived from mouse embryonic stem (ES) cells and in developing mouse embryos. We found that miR-126 regulated the response of endothelial cells to VEGF. Additionally, knockdown of miR-126 in zebrafish resulted in loss of vascular integrity and hemorrhage during embryonic development. miR-126 functioned in part by directly repressing negative regulators of the VEGF pathway, including the Sprouty-related protein, SPRED1, and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2). Increased expression of Spred1 or inhibition of VEGF signaling in zebrafish resulted in defects similar to miR-126 knockdown. These findings illustrate that a single miRNA can regulate vascular integrity and angiogenesis, providing a new target for modulating vascular formation and function.

Genetic variants within miR-126 and miR-335 are not associated with breast cancer risk

“…MiR-126 is involved in the angiogenesis. It binds to the 3' untranslated region of VEGF and subsequently negatively regulates the VEGF pathway [35,36]. MiR-335 suppresses metastasis and migration through targeting the progenitor cell transcription factor SOX4 and extracellular matrix component tenascin C [23].…”

The regulatory role of microRNAs in angiogenesis‐related diseases

“…miR‐126 is mainly expressed within the vascular ECs, which is highly associated with angiogenesis during normal development and injury healing 46, 47, 48. MiR‐126‐3p and miR‐126‐5p are the two mature strands of the pre‐miR‐126 with cell‐type and strand‐specific function in angiogenesis 49, 50.…”

The correlation of circulating pro‐angiogenic miRNAs’ expressions with disease risk, clinicopathological features, and survival profiles in gastric cancer

“…miR‐20a is also regarded as an oncogene in several cancers such as cervical cancer, non‐small cell lung cancer, and anaplastic thyroid cancer, which raised cancer cells’ proliferation, invasion, and spheroid formation (stem cell ability) via targeting multiple genes including CYLD, ATG7, TIMP2, and LIMK1 40, 41, 42, 43. In addition, miR‐210, which leads to angiogenesis through stimulating VEGF production, is also discovered to be increased in several cancers, which correlates with higher pathological grade and elevated TNM stages, and it acts as an carcinogenic miRNA by stimulating cancer cells’ proliferation, migration, and invasion 17, 44, 45, 46, 47, 48. These studies imply that pro‐angiogenic miRNAs promote tumor development and progression, which serve as biomarkers of cancer risk and monitoring of malignancy degree in various cancers.…”