Short-term disruption of TGF-β signaling in adult mice renders the aorta vulnerable to hypertension-induced dissection
Bo Jiang, Pengwei Ren, Changshun He, Mo Wang, Sae-Il Murtada, María Jesús Ruiz-Rodríguez, Yu Chen, Abhay B. Ramachandra, Guangxin Li, Lingfeng Qin, Roland Assi, Martin A. Schwartz, Jay D. Humphrey, George Tellides
Bo Jiang, Pengwei Ren, Changshun He, Mo Wang, Sae-Il Murtada, María Jesús Ruiz-Rodríguez, Yu Chen, Abhay B. Ramachandra, Guangxin Li, Lingfeng Qin, Roland Assi, Martin A. Schwartz, Jay D. Humphrey, George Tellides
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Research Article Cell biology Vascular biology

Short-term disruption of TGF-β signaling in adult mice renders the aorta vulnerable to hypertension-induced dissection

Abstract

Hypertension and transient increases in blood pressure from extreme exertion are risk factors for aortic dissection in patients with age-related vascular degeneration or inherited connective tissue disorders. Yet, a common experimental model of angiotensin II–induced aortopathy in mice appears independent of high blood pressure, as lesions do not occur in response to an alternative vasoconstrictor, norepinephrine, and are not prevented by cotreatment with a vasodilator, hydralazine. We investigated vasoconstrictor administration to adult mice following 1 week of disrupted TGF-β signaling in smooth muscle cells (SMCs). Norepinephrine increased blood pressure and induced aortic dissection by 7 days and even within 30 minutes (as did angiotensin II) that was prevented by hydralazine. Initial medial injury manifested as blood extravasation among SMCs and fibrillar matrix, progressive delamination from accumulation of blood, and stretched or ruptured SMCs with persistent attachments to elastic fibers. Altered regulatory contractile molecule expression was not of pathological importance. Rather, reduced synthesis of extracellular matrix yielded a vulnerable aortic phenotype by decreasing medial collagen, most dynamically basement membrane–associated multiplexin collagen, and impairing cell-matrix adhesion. We conclude that transient and sustained increases in blood pressure can cause dissection in aortas rendered vulnerable by inhibition of TGF-β–driven extracellular matrix production by SMCs.

Authors

Bo Jiang, Pengwei Ren, Changshun He, Mo Wang, Sae-Il Murtada, María Jesús Ruiz-Rodríguez, Yu Chen, Abhay B. Ramachandra, Guangxin Li, Lingfeng Qin, Roland Assi, Martin A. Schwartz, Jay D. Humphrey, George Tellides

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Figure 5

Limited impairment of bulk biomechanical properties 1 week after disrupting TGF-β signaling in mature aortas.

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Limited impairment of bulk biomechanical properties 1 week after disrupt...
Vessel-level biomechanical testing was performed on ascending aortas from untreated B6 WT mice and noninfused or 7-day NE–infused Tgfbr1/2iSMCKO mice. There were 2 classes of tests performed: “active” and “passive.” During active tests, each vessel was held at its individual axial stretch and common luminal pressure of 90 mmHg when exposed to vasoactive agonists. During passive tests, vessels were cyclically pressurized 10–140 mmHg while held at 1 of 3 specimen-specific axial stretches, and then cyclically stretched axially while held at 1 of 4 different common pressures. Data from these 7 protocols were used to calculate material parameters describing the wall mechanics for each vessel. (A) Outer diameter, wall thickness, axial and circumferential (circ) stretch, mean wall stress, and material stiffness, distensibility, and stored energy at group-specific systolic pressures (107 mmHg for B6 WT, 108 mmHg for Tgfbr1/2iSMCKO, and 147 mmHg for Tgfbr1/2iSMCKO + NE). (B) Unpressurized ascending aortas from NE-infused Tgfbr1/2iSMCKO mice without or with dissection (arrow). (C) Overlapping pressure-radius and circumferential stress-stretch curves among the 3 groups. (D) Vasoconstriction, against a fixed pressure at the in vivo axial stretch, responses to KCl and phenylephrine (PE) assessed by reduction of normalized inner radius over time. (E) Steady-state change in inner radius in response to KCl and PE. Data are shown as individual values with mean ± SEM (A and E) or mean ± SEM with connecting lines (C and D). n = 3–4 per group, NE infusion resulted in no dissection (open red symbols, n = 2) or dissection (filled red symbols, n = 2). *P < 0.05 by 1‑way ANOVA with Tukey’s multiple-comparison test (A and E) or Kruskal-Wallis test with Dunn’s multiple-comparison test (A: wall thickness and axial stiffness).