TIMAP 是内皮细胞主导的蛋白磷酸酶 1β 调节亚基，也称为 PPP1R16B，可促进体外内皮细胞增殖和血管生成。 TIMAP 最初被确定为 TGF-β1 介导的抑制靶标，但调节其在内皮细胞中表达的分子途径尚不明确。本研究考察了 BMP9、缺氧和血管生成生长因子在 TIMAP 表达调节中的作用，并确定 TIMAP 是否在体内肿瘤血管生成和生长中发挥作用。 BMP9 有效激活内皮细胞中的 SMAD1/5/8 通路，显着降低 TIMAP mRNA 和蛋白表达。相反，缺氧和脯氨酰羟化酶抑制剂 Roxadustat 通过抑制 BMP9 途径提高 TIMAP mRNA 和蛋白质水平。血管生成生长因子，其中最重要的是 VEGFA 和 IGF-I，部分通过减弱 BMP9 通路激活，但也通过 BMP 通路独立机制来提高内皮 TIMAP 水平。培养的乳腺癌 E0771 细胞释放的介质可提高内皮细胞中 TIMAP 的表达，而 VEGF 抑制剂舒尼替尼 (Sunitinib) 与 IGF-1 抑制剂鬼臼苦素 (Picropodophyllin) 联用可抑制这种作用。在小鼠 E0771 体内乳腺癌模型中，与野生型同窝小鼠相比，TIMAP 缺陷的肿瘤生长和肿瘤血管生成明显减弱。这些发现表明，TIMAP 在体内肿瘤血管生成过程中发挥着关键的促血管生成功能，可能是通过缺氧驱动的 BMP9 通路抑制以及肿瘤细胞对血管生成生长因子的加工来实现的。

TIMAP, the endothelial cell-predominant protein phosphatase 1β regulatory subunit also known as PPP1R16B, promotes in vitro endothelial cell proliferation and angiogenic sprouting. TIMAP was first identified as a target of TGF-β1 mediated repression, but the molecular pathways regulating its expression in endothelial cells are not well-defined. This study examined the role of BMP9, hypoxia and angiogenic growth factors in the regulation of TIMAP expression and determined whether TIMAP plays a role in tumor angiogenesis and growth in vivo. BMP9, which potently activated the SMAD1/5/8 pathway in endothelial cells, significantly reduced TIMAP mRNA and protein expression. Conversely, hypoxia and the prolyl hydroxylase inhibitor Roxadustat raised TIMAP mRNA and protein levels by inhibiting the BMP9 pathway. Angiogenic growth factors, most prominent among them VEGFA and IGF-I, raised endothelial TIMAP levels partly by attenuating BMP9 pathway activation, but also through BMP pathway-independent mechanisms. Cultured breast cancer E0771 cells released mediators that raised TIMAP expression in endothelial cells, effects that were inhibited by the VEGF inhibitor Sunitinib in conjunction with the IGF-1 inhibitor Picropodophyllin. In the mouse E0771 breast cancer model in vivo, tumor growth and tumor angiogenesis were markedly attenuated in TIMAP deficient, compared to wild-type littermates. These findings indicate that TIMAP plays a critical pro-angiogenic function during tumor angiogenesis in vivo, likely through hypoxia-driven inhibition of the BMP9 pathway and through elaboration of angiogenic growth factors by tumor cells.