Key result
GRK2 deficiency in vascular smooth muscle cells exacerbates angiotensin II-induced aortic aneurysm formation by increasing vascular inflammation and promoting TGFβRII degradation.
Why the study?
Whether vascular smooth muscle cell-specific GRK2 deletion exacerbates aortic aneurysm formation remained unproven, prompting investigation into its involvement through TGFβRII degradation and inflammation.
Does GRK2 deficiency in vascular smooth muscle cells exacerbate angiotensin II-induced aortic aneurysm formation?
Does GRK2 deficiency in vascular smooth muscle cells exacerbate angiotensin II-induced aortic aneurysm formation?
Absolute Event Rate: 83.3% vs 0%
GRK2 deficiency in vascular smooth muscle cells exacerbates AngII-induced aortic aneurysm formation by promoting TGFβRII degradation and increasing vascular inflammation, identifying GRK2 as a potential therapeutic target.
Hypothesis-generating for GRK2 in aneurysm pathogenesis; human studies required before therapeutic consideration.
Aortic aneurysm is a life-threatening complication of hypertension-induced cardiovascular dysfunction. Accumulating evidence has proven that G protein-coupled receptor kinase 2 (GRK2) is an important regulator of vascular remodelling and blood pressure. Genetic testing has shown that the expression of transforming growth factor-β type II receptor (TGFβRII) differs significantly between normal and aneurysm tissues. However, no evidence has proven that vascular smooth muscle cell (VSMC)-specific GRK2 deletion exacerbates aortic aneurysm formation. This study aimed to prove the involvement of GRK2 deficiency in aortic aneurysm pathogenesis n a manner dependent on TGFβRII degradation and increased inflammation. We found that GRK2 was downregulated in aneurysm tissues from patients with aortic dissection. Then, mice with VSMC-specific GRK2 deletion were implanted with a micro-osmotic pump containing angiotensin II (AngII) to induce hypertension. GRK2 deficiency led to an increased occurrence of aortic aneurysms, with a decrease in the TGFβR2II level, which enhanced elastin degradation and increased macrophage infiltration. We used adeno-associated virus to overexpress GRK2 in VSMCs in ApoE knock-out (ApoE-/-) mice. Upregulation of GRK2 significantly inhibited the expression of TGFβRII and alleviated aortic aneurysm progression. In vitro, knock-down of GRK2 reduced the cell membrane distribution of TGFβRII by promoting its ubiquitination. Moreover, conditioned medium (CM) from VSMCs with or without adenovirus-mediated GRK2 overexpression in the presence of AngII were used to stimulate macrophages. AngII-induced inflammation was reversed after treatment with CM from VSMCs treated with adenovirus. These findings also indicated an important and novel therapeutic strategy to inhibit aortic aneurysm progression.
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Chen et al. (2023) studied Aortic aneurysm. GRK2 deficiency (knock-down or VSMC-specific knock-out) vs. Control mice with AngII infusion alone was evaluated on Abdominal aortic aneurysm occurrence rate. GRK2 deficiency in vascular smooth muscle cells exacerbates angiotensin II-induced aortic aneurysm formation by increasing vascular inflammation and promoting TGFβRII degradation.
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