Carmen Halabi, M.D., Ph.D.

Assistant Professor

Developmental, Regenerative and Stem Cell Biology Program
Molecular Cell Biology Program
Molecular Genetics and Genomics Program

  • 314-286-1376

  • 314-286-2841

  • McDonnell Pediatric Research Building, 4th floor, Entry 3



  • Understanding how the extracellular matrix (ECM) contributes to normal arterial development and how its disruptionleads to abnormal vascular development and disease

Research Abstract:

With the appearance of vertebrates, there was a dramatic change in cardiovascular design that included a multi-chambered heart within a closed circulatory system. This unique circulatory network facilitated tissue perfusion over longer distances with greater efficiency than possible with open circulation. Key to this circulatory efficiency was a complete retooling of blood vessels driven by the appearance of smooth muscle cells (SMCs), endothelial cells, and elastic fibers - all of which are unique to vertebrates. Elastic fibers confer elasticity to large conduit arteries, which reduces the load on the heart and dampens the pulse pressure generated by each heartbeat by storing energy during systole and releasing it during diastole, i.e. the Windkessel effect. Mature vascular elastic fibers are produced by SMCs and are mainly composed of tropoelastin, the soluble elastin precursor molecule, and microfibrils, composed of fibrillin-1 and/or -2. Assembly of elastin into a functional fiber is a complex process that involves interactions between tropoelastin (the monomeric form of elastin), numerous microfibrillar proteins, and the crosslinking enzyme lysyl oxidase (LOX). Mutations in any of these elastic fiber proteins lead to vascular disease, but only elastin, LOX, and fibulin-4 (FBLN4) result in lethality when deleted. Similar to Lox knock-out (Lox-/-) mice, Fbln4-/- mice die perinatally from cardiopulmonary collapse due to the absence of intact elastic fibers. Furthermore, mutations in FBLN4 and LOX are linked to diseases associated with aneurysm formation in humans. These findings, together with in vitro studies, suggest a functional link between LOX and FBLN4, but how these proteins work together to affect elastin assembly remains unknown.

To better understand the role of FBLN4 in elastogenesis and to study how human mutations affect FBLN4 function, I have characterized a mouse model carrying a disease-causing mutation in Fbln4. Mutant mice developed large artery stiffness and hypertension. In addition, they had ascending aortic aneurysms and arterial tortuosity with significant arterial wall abnormalities including elastic fiber fragmentation and smooth muscle cell disarray. Surprisingly, the elastic fiber abnormalities were seen in large conduit arteries, but not in muscular arteries, suggesting that the process of elastic fiber formation (previously thought to be the same in all vessels) differs between the two vascular beds. These observations form the basis of my research program, which is to:

1. Study the role of FBLN4 in elastic fiber formation by assessing its potential interaction with LOX.
2. Investigate the differences in elastic fiber/vessel development between conduit and muscular arteries.
3. Determine the molecular mechanisms for the development of hypertension and aneurysms in mice with mutant FBLN4.

Mentorship and Commitment to Diversity Statement:
We are committed to fostering an equitable, inclusive and diverse environment not only in the lab, but also in our community as a whole.

Selected Publications:

Troia A, Knutsen RH, Halabi CM, Malide D, Yu ZX, Wardlaw-Pickett A, Kronquist EK, Tsang KM, Kovacs A, Mecham RP, Kozel BA. Inhibition of NOX1 mitigates blood pressure increases in elastin insufficiency. Function. 2021; 2(3): zqab015,

Halabi CM, Hulbert ML. Sickle cell disease-Under pressure. Pediatr Blood Cancer. 2021;68(5):e28932. PMID:33559325

Zhang H, Hanson AM, Scherf de Almeida TU, Emfinger CH, McClenaghan C, Harter T, Yan Z, Cooper PE, Brown GS, Arakel EC, Mecham RP, Kovacs A, Halabi CM, Schwappach B, Remedi MS, Nichols CG. Complex consequences of Cantu Syndrome SUR2 variant R1154Q in genetically modified mice. JCI Insight. 2021;6(5):e145934. PMID:33529173

Halabi CM, Kozel BA. Vascular elastic fiber heterogeneity in health and disease. Curr Opin Hematol. 2020;27(3):190-196. PMID:32141894

McClenaghan C, Huang Y, Yan Z, Harter T, Halabi CM, Chalk R, Kovacs A, van Haaften G, Remedi MS, Nichols CG. Glibenclamide reverses cardiovascular abnormalities of Cantu Syndrome driven by KATP channel overactivity. J Clin Invest. 2020;130(3):1116-21. PMID:31821173

Lee VS, Halabi CM, Broekelmann TJ, Trackman PC, Stitziel NO, Mecham RP. Intracellular retention of mutant lysyl oxidase leads to aortic dilation in response to increased hemodynamic stress. JCI Insight. 2019;5. PMID:31211696 

Huang Y, McClenaghan C, Harter TM, Hinman K, Halabi CM, Matkovich SJ, Zhang H, Brown GS, Mecham RP, England SK, Kovacs A, Remedi MS, Nichols CG. Cardiovascular consequences of KATP overactivity in Cantu syndrome. JCI Insight. 2018;3(15). PMID:30089727 

Shepherd AJ, Mickle AD, Golden JP, Mack MR, Halabi CM, de Kloet AD, Samineni VK, Kim BS, Krause EG, Gereau RW 4th, Mohapatra DP. Macrophage angiotensin II type 2 receptor triggers neuropathic pain. Proc Natl Acad Sci U S A. 2018. PMID:30082378 

Halabi CM, Mecham RP. Elastin purification and solubilization. Methods Cell Biol. 2018;143:207-222. PMID:29310779 

Halabi CM, Broekelmann TJ, Lin M, Lee VS, Chu ML, Mecham RP. Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries. Sci Adv. 2017;3(5):e1602532. PMID:28508064 

Lee VS, Halabi CM, Hoffman EP, Carmichael N, Leshchiner I, Lian CG, Bierhals AJ, Vuzman D, Brigham Genomic Medicine, Mecham RP, Frank NY, Stitziel NO. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc Natl Acad Sci U S A. 2016;113(31):8759-64. PMID:27432961

Halabi CM, Broekelmann TJ, Knutsen RH, Ye L, Mecham RP, Kozel BA. Chronic antihypertensive treatment improves pulse pressure but not large artery mechanics in a mouse model of congenital vascular stiffness. Am J Physiol Heart Circ Physiol. 2015;309(5):H1008-16. PMID:26232234

Last Updated: 6/28/2021 9:33:56 PM

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